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entitled 'Influenza Pandemic: Efforts Under Way to Address Constraints
on Using Antivirals and Vaccines to Forestall a Pandemic' which was
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Report to Congressional Requesters:
United States Government Accountability Office:
GAO:
December 2007:
Influenza Pandemic:
Efforts Under Way to Address Constraints on Using Antivirals and
Vaccines to Forestall a Pandemic:
GAO-08-92:
GAO Highlights:
Highlights of GAO-08-92, a report to congressional requesters.
Why GAO Did This Study:
Pandemic influenza poses a threat to public health at a time when the
United Nations’ World Health Organization (WHO) has said that
infectious diseases are spreading faster than at any time in history.
The last major influenza pandemic occurred from 1918 to 1919. Estimates
of deaths worldwide if a similar pandemic were to occur have ranged
between 30 million and 384 million people. Individual countries and
international organizations have developed and begun to implement a
strategy for forestalling (that is, containing, delaying, or minimizing
the impact of) the onset of a pandemic. Antivirals and vaccines may
help forestall a pandemic.
GAO was asked to examine
(1) constraints upon the use of antivirals and vaccines to forestall a
pandemic and (2) efforts under way to overcome these constraints. GAO
reviewed documents and consulted with officials of the Departments of
State and Health and Human Services (HHS), international organizations,
and pharmaceutical manufacturers.
WHO commented that the report was comprehensive and useful. HHS
stressed that vaccines and antivirals must be viewed in a larger
context. State and HHS commented that the term “forestall” is ambiguous
and misleading. However, GAO has used the word in a way that is
consistent with WHO’s use of the term.
What GAO Found:
The use of antivirals and vaccines, two elements of the international
strategy to forestall a pandemic, could be constrained by their
uncertain effectiveness and limited availability. To use antivirals
effectively, health authorities must be able to detect a pandemic
influenza strain quickly through surveillance and diagnostic efforts
and use this information to administer antivirals. The effectiveness of
antivirals could be limited if they are used more than 48 hours after
the onset of symptoms or by the emergence of strains resistant to
antivirals. Unlike antivirals, vaccines are formulated to target a
specific influenza strain in advance of infection. The effectiveness of
vaccines in forestalling a pandemic could be limited because such a
targeted pandemic vaccine cannot be developed until that strain has
been identified. Due to the time required to identify the virus and
develop and manufacture a pandemic vaccine—20 to 23 weeks according to
HHS—such vaccines are likely to play little or no role in efforts to
forestall a pandemic in its initial phases. The availability of
antivirals and vaccines in a pandemic could be inadequate due to
limited production, distribution, and administration capacity. WHO has
stated that it is unlikely that sufficient quantities of antivirals
will be available in any country at the onset of a pandemic. The
distribution and administration capacity for antivirals and vaccines is
limited in some countries by poor or nonexistent delivery plans and
networks, a lack of facilities for administering the drugs, and small
numbers of personnel trained to administer them.
The United States, its international partners, and the pharmaceutical
industry are investing substantial resources to address constraints on
the availability and effectiveness of antivirals and vaccines. Efforts
are under way to improve influenza surveillance, including diagnostic
capabilities, so that outbreaks can be quickly detected. Increased
demand and government support has led manufacturers to increase
research into more effective antivirals and vaccines. Manufacturers are
developing new antivirals to combat influenza. New methods for
developing vaccines are being studied in order to reduce the amount of
vaccine that is needed and to increase the number of strains against
which it is effective. Pre-pandemic vaccines, which are formulated to
target influenza strains that have the potential to cause a pandemic,
are being developed. However, these vaccines may or may not be
effective against the pandemic strain that ultimately emerges. To
overcome limitations on the availability of antivirals and vaccines,
manufacturers are working to increase production at existing facilities
and build new facilities. To address constraints on the distribution
and administration of antivirals, stockpiles are being established to
allow faster delivery of antivirals to countries experiencing
outbreaks. WHO is also working to establish stockpiles of pre-pandemic
vaccines. Additionally, other efforts also face limitations. For
example, increasing production capacity of vaccines and antivirals will
take several years as new facilities are built and necessary materials
acquired.
To view the full product, including the scope and methodology, click on
[hyperlink, http://www.GAO-08-92]. For more information, contact Marcia
Crosse at (202) 512-7114 or crossem@gao.gov, or David Gootnick at (202)
512-3149 or gootnickd@gao.gov.
[End of section]
Contents:
Letter:
Results in Brief:
Background:
Uncertain Effectiveness and Limited Availability Would Likely Constrain
the Use of Antivirals and Vaccines to Forestall the Onset of a Pandemic:
U.S. Government and International Partners' Efforts Are Under Way to
Address Constraints on Use of Antivirals and Vaccines, but Certain
Efforts Face Limitations:
Agency Comments and Our Evaluation:
Appendix I: Comments from the Department of Health and Human Services:
Appendix II: Comments from the Department of State:
Appendix III: GAO Contacts and Staff Acknowledgments:
Related GAO Products:
Tables:
Table 1: Influenza Vaccine Types:
Table 2: Antiviral Drugs Available for the Prevention and Treatment of
Influenza:
Table 3: HHS Contracts Awarded to Companies in December 2006 to Develop
Rapid Diagnostic Tests for Influenza:
Table 4: HHS Contracts Awarded in May 2006 to Develop Cell-Based
Vaccines:
Table 5: HHS Contracts Awarded in January 2007 to Develop Influenza
Vaccines Containing an Adjuvant:
Figure:
Figure 1: Pandemic Vaccine Production Timeline:
Abbreviations:
CDC: Centers for Disease Control and Prevention:
FAO: Food and Agriculture Organization of the United Nations:
FDA: Food and Drug Administration:
GLEWS: Global Early Warning and Response System for Major Animal
Diseases, including Zoonoses:
HHS: Department of Health and Human Services:
IFPMA: International Federation of Pharmaceutical Manufacturers &
Associations:
NIH: National Institutes of Health:
OFFLU: OIE/FAO Network of Expertise on Avian Influenza:
OIE: World Organisation for Animal Health (Office International des
Epizooties):
WHO: United Nations' World Health Organization:
United States Government Accountability Office:
Washington, DC 20548:
December 21, 2007:
The Honorable Edward M. Kennedy:
Chairman:
Committee on Health, Education, Labor and Pensions:
United States Senate:
The Honorable Daniel K. Akaka:
Chairman:
Subcommittee on Oversight of Government Management, the Federal
Workforce, and the District of Columbia:
Committee on Homeland Security and Governmental Affairs:
United States Senate:
The Honorable Bennie G. Thompson:
Chairman:
Committee on Homeland Security:
House of Representatives:
The Honorable Judd Gregg:
United States Senate:
An influenza pandemic--caused by a novel strain of influenza virus that
is virulent and highly transmissible among humans--would be of global
significance. While some scientists and public health experts believe
that the next influenza pandemic could be caused by a strain of the
H5N1 avian influenza virus (also known as "bird flu") that is currently
circulating in parts of Asia, Europe, and Africa, it is unknown when an
influenza pandemic will occur, where it will begin, or whether an H5N1
strain or another strain would be the cause. Pandemic influenza poses a
grave threat to global public health at a time when the United Nations'
World Health Organization (WHO) has said that infectious diseases are
spreading faster than at any time in history. Of the three pandemics of
the twentieth century, the most deadly was the pandemic of 1918-1919 in
which scientists estimate that there were 50-100 million deaths
worldwide, including at least 675,000 in the United States, making it
among the most deadly events in human history. The U.S. government has
estimated that as many as 2 million U.S. citizens could die in the next
pandemic. If an influenza pandemic were to occur on the same scale as
the 1918-1919 pandemic, estimates of deaths worldwide have ranged
between 30 million and 384 million people.
The concern regarding an influenza pandemic has prompted the United
States, other governments, and international organizations such as WHO
to develop and begin to implement an international strategy to respond
to the threat of an influenza pandemic.[Footnote 1] The international
strategy comprises local, national, regional, and global strategies,
which include a variety of countermeasures designed to contain or delay
a pandemic or to minimize its impact once it emerges. Included among
the elements of these strategies aimed at forestalling a pandemic (that
is, containing, delaying, or minimizing the impact of) are antivirals
and vaccines. Both could potentially be used to prevent infection and,
in the case of antivirals, to also treat infected individuals.[Footnote
2]
The important role that antivirals and vaccines could play in
containing or limiting the spread of a pandemic has led to questions
regarding their use. For example, antivirals and vaccines could be
needed in greater quantities than ever before. As agreed with your
offices, we are reporting on (1) the constraints upon the use of
antivirals and vaccines to forestall the onset of a pandemic and (2)
the efforts under way to overcome these constraints.
To report on these issues, we reviewed documents and consulted
officials from the Departments of Health and Human Services (HHS) and
State, WHO, the Asian Development Bank, and pharmaceutical
manufacturers.[Footnote 3] Within HHS, we examined documents and
consulted officials from the Office of the Secretary, the Centers for
Disease Control and Prevention (CDC), the Food and Drug Administration
(FDA), and the National Institutes of Health (NIH). We obtained
information from the International Federation of Pharmaceutical
Manufacturers & Associations (IFPMA), including information about
influenza vaccine development projects initiated by members of its
Influenza Vaccine Supply International Task Force.[Footnote 4] We
reviewed reports published by the Institute of Medicine focusing on
pandemic influenza. In addition, we interviewed experts and attended
academic symposia on pandemic influenza and the challenges to
addressing its threat. We determined the data on the funding of
antiviral and vaccine research as well as the data on the
manufacturing, use, and availability of antivirals and vaccines were
sufficiently reliable for the purposes of this report. Our goal in
collecting the information in this report was to provide a picture of
ongoing efforts by the U.S. government, other national governments,
international organizations like WHO, and industry to prepare for a
pandemic. This often involved reporting technical information on the
research and development on antivirals and vaccines. In some cases,
rapid scientific advances may have outpaced the timing of this report
such as, for example, the initiation of a new area of research not
specifically identified in the report. In other cases, there is no
consensus on the appropriate use and likely results of various medical
countermeasures, including different types of antivirals and vaccines.
This report was not intended to provide the most complete, current, or
definitive discussion of scientific developments and knowledge
concerning the use of antivirals and vaccines. We have, instead, sought
to report information that is necessary to understand the challenges
faced by the U.S. government and others in their efforts to develop
measures involving antivirals and vaccines in efforts to forestall a
pandemic. We conducted our work from January 2006 through December 2007
in accordance with generally accepted government auditing standards.
In recent related work, we examined the extent to which U.S. agencies
and their international partners have assessed pandemic risk by country
and prioritized countries for international assistance. In addition, we
examined the steps that U.S. agencies and their international partners
have taken to improve global preparedness to forestall a pandemic.
[Footnote 5] This work was also conducted in accordance with generally
accepted government auditing standards.
Results in Brief:
The use of antivirals and vaccines to forestall the onset of a pandemic
would likely be constrained by their uncertain effectiveness and
limited availability. Health authorities must be able to detect the
virus strain quickly through surveillance and diagnostic efforts and
use this information to test and administer effective antivirals. The
effectiveness of antivirals could be limited if they are used more than
48 hours after the onset of symptoms and by the emergence of influenza
strains that are resistant to antivirals. Due to the time required to
detect the virus and develop and manufacture a targeted vaccine for a
pandemic--about 20 to 23 weeks according to HHS--pandemic vaccines are
likely to play little or no role in efforts to stop or contain a
pandemic, at least in its initial phases. Furthermore, weaknesses in
the global influenza surveillance system, including weaknesses in
diagnostic capability, could limit the effectiveness of antivirals and
vaccines in treating and preventing cases of infection because of
limitations in many countries that impede the detection of influenza
strains. In addition, the supply of antivirals and vaccines available
in the event of a pandemic would probably be inadequate due to limited
production, distribution, and administration capacity. WHO has stated
that it is unlikely that sufficient quantities of antivirals will be
available in any country at the onset of a pandemic. The supply of
pandemic vaccine would likely not be able to meet demand without
additional production capacity, achieved either by current
manufacturers scaling up production or by increasing the number of
manufacturers. The distribution and administration capacity for
antivirals and vaccines is limited in some countries by poor or
nonexistent delivery plans and networks, a lack of facilities suitable
for administering the drugs, and small numbers of personnel trained to
administer them.
The United States, its international partners, and the pharmaceutical
industry are investing substantial resources to address constraints on
the availability and effectiveness of antivirals and vaccines, but some
of these efforts face limitations and are not expected to produce
results for several years. To better ensure the effectiveness of
antivirals and vaccines by being able to quickly identify a pandemic
strain, the United States and its international partners are involved
in efforts to improve influenza surveillance, including diagnostic
capability. WHO's revised International Health Regulations seek to
minimize the international spread of disease, in part by improving
disease surveillance in humans. International surveillance networks for
influenza in animals have been established and efforts are under way to
improve data sharing among scientists. However, WHO and HHS officials
have raised concerns regarding Indonesia's refusal to share influenza
samples and how this could harm global public health. Indonesia has
refused to consistently share influenza samples because of concerns
that the resulting vaccines would not be available to developing
countries and from a desire for royalties from any invention derived
from an influenza sample isolated within its borders. Increased demand
and government support have encouraged manufacturers to increase their
research and development into more effective antivirals and vaccines.
For example, the U.S. government awarded a $103 million contract to one
company to develop a new antiviral. The United States also has awarded
approximately $1.1 billion to companies to develop a new influenza
vaccine production technology that would expand vaccine manufacturing
capacity in the United States. Alternative methods for developing
vaccines are also being studied in order to reduce the amount of
vaccine that is needed to provide protection and to increase the number
of strains against which a vaccine is effective. Pre-pandemic vaccines,
which are formulated to target influenza strains that have the
potential to cause a pandemic, are being developed. However, these
vaccines may or may not be effective against the pandemic strain that
ultimately emerges. To overcome limitations on the availability of
effective antivirals and vaccines, national governments and
international organizations are working with pharmaceutical
manufacturers to expand global production capacity to increase
production at facilities and build new production facilities. To
address constraints on the distribution and administration of
antivirals, international organizations and pharmaceutical
manufacturers have established global and regional antiviral stockpiles
to deliver these drugs more quickly to countries experiencing
outbreaks. WHO has recently begun to establish a pre-pandemic vaccine
stockpile for use in countries without influenza production capacity or
the ability to purchase vaccines. Several industrialized countries,
including the United States, have established pre-pandemic influenza
vaccine stockpiles to vaccinate critical workforce and primary health
care workers at the onset of a pandemic. However, some of these efforts
face limitations. For example, increasing global production capacity of
vaccines and antivirals will take several years as new production
facilities are built, materials necessary for production are acquired,
and the necessary approval is received to market these medical products
in various countries.
In commenting on a draft of this report, WHO provided comments via e-
mail and stated that the report was comprehensive and useful. HHS
stressed that vaccines and antivirals should be viewed in the context
of a broader pandemic strategy. The Departments of State and HHS
commented that the term "forestall" is ambiguous and misleading.
However, we have defined the term in a way that is consistent with how
WHO has used the word in describing its efforts to respond to a
pandemic. We defined the term to mean contain, delay, or minimize the
impact of a pandemic.
Background:
WHO, in conjunction with the United States and other governments, has
developed an international strategy for forestalling the onset of an
influenza pandemic. Elements of this strategy include restricting the
movement of people in and out of the affected area, isolation of ill
persons, and school closures. Antivirals are also an important element
of this strategy. Studies suggest that using antiviral drugs, along
with other interventions, to treat infections and prevent illness might
contain a pandemic at the site of the outbreak or at least slow its
international spread, thus gaining time to put emergency measures in
place and begin producing matched vaccines that would be effective in
preventing individuals from being infected with the strain of influenza
causing the pandemic.
Influenza:
Influenza, also called "the flu," is caused by a virus that primarily
attacks the upper respiratory tract--the nose and throat--and sometimes
the lungs. Influenza is characterized by cough, fever, headache, and
other symptoms and is more severe than some viral respiratory
infections, such as the common cold. In almost every year a seasonal
influenza virus causes acute respiratory disease in epidemic
proportions somewhere in the world.[Footnote 6] Most people who
contract seasonal influenza recover completely in 1 to 2 weeks, but
some develop serious and potentially life-threatening medical
complications, such as pneumonia.[Footnote 7] Most healthy adults may
infect others 1 day before getting symptoms and up to 5 days after they
first develop symptoms. Some young children and people with weakened
immune systems may be contagious for more than a week. WHO estimates
that seasonal influenza affects about 5 to 15 percent of the world's
population each year, causing 3 to 5 million cases of severe illness
worldwide including 250,000 to 500,000 deaths.
There are three types of influenza viruses: A, B, and C. However, only
influenza A viruses cause pandemics.[Footnote 8] Influenza A viruses
are further categorized into subtypes according to differences in the
"HA" and "NA" proteins that are on the outer surface of the
virus.[Footnote 9] These influenza A subtypes are further characterized
into strains. Influenza strains mutate, or genetically change, over
time. As strains mutate, new strains of influenza viruses appear and
may replace older, circulating strains. When a new strain of human
influenza virus emerges, immunity that may have developed after a
previous infection or vaccination may not provide protection against
the new strain. Small mutations in the influenza virus are the reason
why someone who has previously been infected with influenza can still
be susceptible to seasonal or common influenza. More substantial
changes in the influenza virus can result in the emergence of a
pandemic influenza subtype.[Footnote 10]
Pandemic human influenza is a virulent influenza that causes a global
outbreak, or pandemic, of serious illness. It occurs when an existing
strain of the influenza virus is replaced by a new influenza A strain
to which humans have no immunity, resulting in widespread morbidity and
mortality.[Footnote 11] According to WHO, pandemic influenza can spread
to all parts of the world very quickly, usually in less than a year,
and can sicken more than a quarter of the global population.[Footnote
12] Three conditions must be met before an influenza pandemic begins:
(1) a new influenza virus subtype that has not previously, or at least
recently, circulated in humans must emerge, (2) the virus must be
capable of causing disease in humans, and (3) the virus must be capable
of sustained human-to-human transmission. The H5N1 virus currently
meets the first two of these three conditions but not the
third.[Footnote 13]
The current H5N1 pandemic influenza threat stems from an unprecedented
outbreak of H5N1 influenza that first appeared in birds in southeastern
China and Hong Kong in 1996 and 1997 and was first detected in humans
in Hong Kong in 1997. The virus reappeared in late 2003 and early 2004
and has since spread in bird populations across parts of Asia, Europe,
and Africa, with limited infections in humans.[Footnote 14] From
December 1, 2003, to December 11, 2007, H5N1 was detected in animals in
60 countries. According to WHO, the geographical spread of H5N1 in
animals in 2006 was the fastest and most extensive of any pathogenic
avian influenza virus recorded to date. From January 1, 2003, through
December 12, 2007, WHO reported 338 confirmed human cases, including
208 human deaths from the H5N1 virus in a total of 12 countries--a case
fatality rate of 62 percent.[Footnote 15] Scientists and public health
officials agree that the spread of the H5N1 virus in birds and the
occurrence of infections in humans have increased the risk that this
disease may change through adaptive mutation or reassortment into a
form that is easily transmissible among humans, resulting in an
influenza pandemic.[Footnote 16]
HHS stated that little is known about how to control a pandemic and
that it is important to distinguish between seasonal influenza and
pandemic influenza. Current knowledge about how antiviral drugs and
influenza vaccines perform is largely drawn from experience with
seasonal influenza. HHS stated that how antivirals and vaccines will
perform against a pandemic influenza virus cannot be predicted, but as
there are currently no better options, the agency has made plans for
their use in response to a pandemic.
Vaccines:
Vaccines are considered the first line of defense against influenza to
prevent infection and control the spread of the disease. Vaccines
stimulate immune responses which include causing the body to produce
neutralizing antibodies to provide protective immunity to a particular
virus strain.[Footnote 17] After vaccination, the body takes about 2
weeks to produce protective antibodies for that strain. For the one FDA-
licensed H5N1 vaccine, two doses administered about 4 weeks apart would
be required to provide what is believed to be an adequate immune
response based on past experience with seasonal influenza vaccines.
When a vaccinated person is exposed to the specific virus proteins in
the vaccine, antibodies develop in response that will help either to
prevent infection or reduce the severity of the illness caused by
infection.[Footnote 18] To be most effective, an influenza vaccine
needs to closely match the circulating influenza strain. However,
because influenza viruses undergo minor but continuous genetic changes
from year to year, a matched vaccine cannot be developed until the
circulating strain has been identified. Generally, the purpose of
vaccination is to prevent infection; however, in the event of a
pandemic, the purpose could be broadened to include decreasing
mortality or morbidity. The impact of such a change could be to
increase vaccine availability since a vaccine that is not fully matched
to the virus might be available more quickly and still help reduce
mortality and morbidity.
In the case of vaccines for seasonal influenza, WHO, CDC, FDA, health
officials around the world, and vaccine manufacturers participate in a
system that develops and produces vaccines targeted to the influenza
strains most likely to be in circulation during the next influenza
season. This system collects and analyzes circulating influenza
viruses, uses the information to determine the three human strains most
likely to circulate in the upcoming year, and formulates and
distributes virus reference strains to vaccine manufacturers, who
produce seed viruses to manufacture influenza vaccines.[Footnote 19]
Influenza vaccine is produced in a complex process that involves
growing viruses in millions of fertilized chicken eggs. Seasonal
vaccine production generally takes 6 or more months after virus strains
have been selected.[Footnote 20] The same general system would be used
in the event of a pandemic to manufacture a vaccine targeted to the
influenza strain causing it.
Influenza vaccines can be categorized into three types: seasonal, pre-
pandemic, and pandemic. As discussed in table 1, seasonal vaccines
protect against annual (i.e., seasonal) influenza strains. Pre-pandemic
vaccines are formulated to match strains of influenza viruses that have
had limited circulation in humans but have pandemic potential. However,
they are not matched or targeted to the specific pandemic strain that
may eventually emerge.[Footnote 21] Pandemic vaccines are formulated to
match a pandemic strain that has already emerged. Influenza vaccines
are made either from inactivated (i.e., killed) viruses or from live
viruses that have been attenuated (i.e., weakened).[Footnote 22]
Generally, inactivated influenza vaccines are made from parts of the
influenza virus rather than the whole virus.
Table 1: Influenza Vaccine Types:
Type: Seasonal;
Definition: A vaccine produced annually that protects against that
year's strains of seasonal influenza. Current seasonal vaccines are
trivalent, meaning they contain three different strains of influenza
viruses.
Type: Pre-Pandemic;
Definition: A vaccine against strains of influenza virus in animals
that have caused isolated infections in humans and have pandemic
potential. This vaccine is prepared prior to the emergence of a
pandemic strain and may be a good or poor match (and hence of greater
or lesser protection) for the pandemic strain that ultimately emerges.
Type: Pandemic;
Definition: A vaccine targeted to a specific novel influenza virus
strain that has the capacity for sustained and efficient human-to-human
transmission. This vaccine can only be developed once the pandemic
strain emerges.
Sources: European Commission and U.S. Homeland Security Council.
[End of table]
Globally, influenza vaccine production is largely a private-sector
activity and vaccine manufacturing is concentrated in Europe and North
America, with approximately 90 percent of worldwide production capacity
located in these areas. However, there are manufacturers throughout the
world, including in Australia, China, and Japan. Some manufacturers
have production facilities in more than one country. In some cases,
more than one manufacturer may be producing vaccine for distribution in
a particular country. For example, there were four manufacturers
producing five vaccines for the 2006-2007 influenza season in the
United States.[Footnote 23] In the event of a pandemic, manufacturers
would switch production from seasonal to pandemic vaccine, and would
use the same facilities to produce the pandemic vaccine as they had
used to produce seasonal vaccine.[Footnote 24] Pre-pandemic vaccines
are currently produced only during the 3-to 4-month period when
manufacturers are not producing seasonal vaccine.
Antivirals:
Antiviral drugs are also used against seasonal influenza in humans to
reduce symptoms and complications and could be used in the event of a
pandemic. Antivirals can be used to both prevent illness and treat
those who are already infected by killing or suppressing the
replication of the influenza virus. Antivirals are not reformulated to
match a specific influenza strain and could be used from the early
phase of an influenza pandemic.
As shown in table 2, two classes of antiviral drugs are currently
available for the prevention and treatment of influenza, and two types
of drugs within each class have been approved. Amantadine and
rimantadine belong to the older class, adamantanes.[Footnote 25]
Tamiflu and Relenza belong to the newer class, neuraminidase
inhibitors.[Footnote 26] Amantadine is given as a capsule, syrup, or
tablet, while rimantadine is administered as a syrup or tablet. Tamiflu
can be administered as either a capsule or liquid. Relenza is a powder
that must be inhaled using a special device. According to CDC,
antivirals are about 70 to 90 percent effective for preventing illness
in healthy adults; that is, they are about as effective as vaccines,
when the vaccine and circulating virus strains are well matched, in
preventing illness among healthy adults. For maximal effectiveness in
preventing infection, the antiviral must be taken throughout the entire
period of a community outbreak. According to current research involving
seasonal influenza, if taken within 2 days of the onset of symptoms,
these drugs can shorten the duration of the illness by 1 or 2 days,
alleviate symptoms, reduce complications and serious illness, and may
make someone with influenza less contagious to others. However, it is
unknown if antivirals will perform the same for pandemic influenza as
they do for seasonal influenza. In addition, influenza virus strains
can become resistant to one or more of these drugs, and so they may not
always be effective for prevention or treatment.[Footnote 27]
Table 2: Antiviral Drugs Available for the Prevention and Treatment of
Influenza:
Class: Adamantanes (M2-ion channel inhibitors);
Scientific name[A]: Amantadine;
Drug name(s)[B]: Symmetrel, Amantadine Hydrochloride;
Route of administration: Oral (capsule, syrup, tablet).
Class: Adamantanes (M2-ion channel inhibitors);
Scientific name[A]: Rimantadine;
Drug name(s)[B]: Flumadine, Rimantadine Hydrochloride;
Route of administration: Oral (syrup, tablet).
Class: Neuraminidase inhibitors;
Scientific name[A]: Oseltamivir;
Drug name(s)[B]: Tamiflu;
Route of administration: Oral (capsule, suspension)[C].
Class: Neuraminidase inhibitors;
Scientific name[A]: Zanamivir;
Drug name(s)[B]: Relenza;
Route of administration: Inhalation (powder).
Sources: HHS and WHO.
[A] The scientific name of a drug is also referred to as the generic
name.
[B] These are the names under which the drug is currently marketed in
the United States.
[C] Suspension is a liquid dosage form that contains solid particles
dispersed in a liquid.
[End of table]
WHO has stated that the neuraminidase inhibitors are preferred for
prevention and treatment of influenza because there is lower risk for
adverse events (compared historically to adamantanes), less evidence of
drug resistance, and greater therapeutic value associated with these
particular antivirals.[Footnote 28] Of the two currently available
neuraminidase inhibitors, WHO strongly recommends the use of Tamiflu.
Tamiflu is generally less expensive and easier to ship than Relenza
and, because it is given as a capsule or liquid, it is easier to
administer.
Pharmaceutical manufacturers are currently producing both brand name
and generic versions of antivirals approved for preventing and treating
influenza. Tamiflu is produced by Roche, a health care company that
sells products throughout the world. Relenza is manufactured by
GlaxoSmithKline, another health care company that sells products
worldwide.[Footnote 29] Neither drug is patent protected in all
countries, so generic drug manufacturers may produce these drugs where
they are not under patent protection.[Footnote 30] Both amantadine and
rimantadine are no longer under patent protection and, consequently,
the number of manufacturers that can produce the drug worldwide is not
limited by patent restrictions.
U.S. Government Entities Engaged in International Pandemic Influenza
Preparedness:
HHS, along with the Departments of Agriculture, Defense, and State and
the U.S. Agency for International Development, carries out U.S.
international animal and pandemic influenza assistance programs. The
Department of State leads the federal government's international
engagement on influenza and coordinates U.S. international assistance
activities through an interagency working group.[Footnote 31] The
Homeland Security Council is monitoring the U.S. efforts to improve
domestic and international preparedness.
HHS provides technical assistance and financing to improve human
disease detection and response capacity. HHS received total
appropriations specifically available for pandemic-influenza-related
purposes in fiscal year 2006 of $5.683 billion.[Footnote 32] Of this
amount, HHS allocated approximately $3.2 billion to vaccines, $1.1
billion to antivirals, and $179 million to international collaboration
with the remainder going to such areas as state and local preparedness
and risk communications.
The U.S. Agency for International Development provides technical
assistance, equipment, and financing for both animal and human health-
related activities. In addition, the Department of Agriculture provides
technical assistance and conducts training and research programs and
the Department of Defense stockpiles protective equipment.
International Strategy to Contain a Pandemic:
WHO, in conjunction with the United States and other governments, has
developed an international strategy on how to contain an emerging
pandemic virus at the site of the outbreak, whether it is H5N1 or
another influenza virus with pandemic potential.[Footnote 33]
Containment is a key element of the broad U.S. National Strategy for
Pandemic Influenza.[Footnote 34] The public health community has
generally not attempted to contain an initial outbreak of a pandemic-
potential strain or to eradicate it while it is still confined to a
limited area.[Footnote 35] WHO has noted that the success of the
strategy in halting a pandemic or delaying its spread cannot be
assured. However, WHO has stated that given the potential health,
economic, and social damage a pandemic can produce, forestalling a
pandemic must be tried. Further, WHO notes that should early
containment fail, once a certain level of spread of the pandemic virus
is reached, no interventions are expected to halt international spread,
and the public health response will need to shift to the reduction of
morbidity and mortality.
The international containment strategy is based on studies suggesting
that efforts, centered on using antiviral drugs to prevent infection as
well as treat cases, might contain a pandemic at the site of the
outbreak or at least slow its international spread, thus gaining time
to put emergency measures in place and develop vaccines.[Footnote 36]
Such a strategy includes the creation of a geographically defined
containment zone. According to WHO, the containment zone would be
created around the cases where widespread antiviral and
nonpharmaceutical countermeasures should be used. The containment zone
should be large enough so that all known persons infected by the
pandemic virus are located within the zone as well as many of the
people in frequent contact with them. Rapid detection and reliable
reporting of outbreaks, immediate availability of necessary antivirals
for large numbers of people, and the restriction of the movement of
people in and out of the affected area (or containment zone) are
components of the strategy. Other elements of the strategy include
isolation of ill persons, voluntary quarantine of people in contact
with these persons, school closures, and cancellation of mass
gatherings. These measures are meant to reduce the opportunities for
additional human-to-human transmission to occur.
Disease surveillance in animals and humans has a critical role in the
success of the international strategy to forestall the onset of a
pandemic. The Director of CDC has stated that for optimal response, an
emerging influenza pandemic outbreak anywhere in the world must be
recognized within 1 to 2 weeks and then be investigated and confirmed
within days. Infectious disease surveillance activities include
detecting and reporting cases of disease, analyzing and confirming this
information to identify possible outbreaks or longer-term trends,
exchanging information related to cases of infectious disease, and
applying the information to inform public health decision-making. HHS
officials have noted that as outbreaks of animal influenza viruses
spread and affect people, collaboration between animal and human
influenza surveillance systems is needed. Additionally, WHO has stated
early detection of animal diseases, which might be transmissible to
humans, leads to quicker actions to reduce threats to humans. Alerts of
animal outbreaks can provide early warning so that human surveillance
can be enhanced and preventive action taken. When effective,
surveillance can facilitate (1) timely action to control disease
outbreaks, (2) informed allocation of resources to meet changing
disease conditions and other public health programs, and (3) adjustment
of disease control programs to make them more effective.
Diagnostic tests are an important component of identifying pandemic
influenza and putting measures in place to forestall its spread.
Diagnostic tests for a range of viruses help assess patients for the
presence of H5N1, other emerging influenza viruses, and seasonal
influenza. Quick and accurate diagnosis of influenza is essential to
early treatment. In addition, accurate, rapid diagnosis enables timely
implementation of containment and treatment procedures, and will be
critical in identifying the beginning of a pandemic and possibly
slowing the spread of the disease. Rapid diagnosis allows more time for
equipment and personnel to be mobilized to aid in pandemic response.
As part of the WHO Global Influenza Surveillance Network, individual
countries, including the United States, collect and analyze influenza
virus samples and submit selected samples to WHO Collaborating Centres
for further analysis.[Footnote 37] These samples allow WHO to perform a
number of influenza-related public health activities, including:
* determining if the virus has acquired human genes or made other
significant changes,
* tracking the evolution of the virus and its geographic spread,
* updating diagnostic tests and reagents,[Footnote 38]
* identifying potential vaccine strains, and:
* testing to determine if the virus remains susceptible to antivirals.
The success of this network is dependent upon the participation of its
members. According to HHS, the network has functioned efficiently in
the past for the detection and characterization of newly emergent
influenza viruses of epidemic potential.
Uncertain Effectiveness and Limited Availability Would Likely Constrain
the Use of Antivirals and Vaccines to Forestall the Onset of a Pandemic:
The use of antivirals and vaccines to forestall the onset of a pandemic
would likely be constrained by their uncertain effectiveness and
limited availability. Weaknesses within the international influenza
surveillance system impede the detection of strains, which could limit
the ability to promptly administer or develop effective antivirals and
vaccines to treat and prevent cases of infection to prevent its spread.
The delayed use of antivirals and the emergence of antiviral resistance
in influenza strains could limit their effectiveness. A targeted
vaccine cannot be manufactured until the pandemic strain has emerged
and been identified. The availability of antivirals and vaccines is
constrained by existing limitations in their production, distribution,
and administration. Current antiviral production capacity is inadequate
to reach the number of antivirals WHO estimates will be needed to
contain a pandemic. Vaccines targeted to match a pandemic strain are
unlikely to be available for prevention of disease at the onset of a
pandemic as, according to HHS officials, they would not become
available until 20 to 23 weeks following detection of a pandemic.
Moreover, most countries do not possess the capacity to distribute and
administer these antivirals and vaccines quickly enough to forestall a
pandemic.
The Effectiveness of Antivirals and Vaccines in Containing Initial
Outbreaks Could Be Constrained by the Limited Capacity to Monitor the
Virus and Successfully Treat and Prevent Cases:
Antiviral and vaccine effectiveness depends upon their timely
application. To achieve timely application, health authorities must be
able to detect the virus strain quickly through surveillance efforts
and use this information to administer or develop effective antivirals
and vaccines. However, weaknesses within the global influenza
surveillance system could limit the effectiveness of antivirals and
vaccines in treating and preventing cases of infection. In addition,
limited support for clinical trials could hinder their ability to
improve understanding of the use of antivirals and vaccines against a
pandemic strain.
The Effectiveness of Antivirals and Vaccines to Forestall a Pandemic
Depends on Influenza Surveillance:
An influenza surveillance system that can promptly detect outbreaks
would facilitate the timely use of antivirals. The effectiveness of
antivirals in containing an initial influenza outbreak of a new strain
depends in part on the timely use of the appropriate drug. Experience
with seasonal influenza indicates that antivirals are most effective
for treatment if started within 48 hours of the onset of symptoms;
therefore, rapid detection of human outbreaks of potential pandemic
strains is necessary. If an individual is diagnosed too late,
antivirals may not be effective. WHO has noted that a critical problem
is the tendency of human H5N1 cases to be detected late in the course
of the illness. Antivirals used for prevention should be started either
before exposure or as soon as possible after initial exposure.
International surveillance is also required to monitor strain evolution
for the development of vaccines targeted to a potential pandemic strain
or the actual pandemic strain. A well-matched vaccine cannot be ensured
until the pandemic virus strain has been identified. According to HHS
officials, 20 to 23 weeks are currently required from the detection of
a pandemic before a well-matched vaccine can be developed.[Footnote 39]
Consequently, well-matched vaccines are likely to play little or no
role in efforts to stop or contain a pandemic, at least in its initial
phases. However, an effective surveillance system is necessary to
develop a safe and effective pandemic vaccine as soon as possible so
that a vaccine is available for later stages of the pandemic.
Another concern is that influenza strains can be resistant to
antivirals, rendering them ineffective in treating or preventing
infection. Monitoring strain evolution to determine susceptibility or
emergence of antiviral resistance is one element of assessing the
likelihood that a particular antiviral will be effective. The
effectiveness of an antiviral against one strain of seasonal influenza
does not mean that it will be effective against an H5N1 strain or
another potential pandemic strain. While both classes of antivirals,
adamantanes and neuraminidase inhibitors, could potentially be used
against a pandemic strain, experts caution against the use of
adamantanes without prior indication that the emerging strain is
susceptible to them. For example, CDC recommends against the use of
adamantanes to treat or prevent currently circulating influenza because
strains resistant to adamantanes have emerged. Similarly, WHO
recommends only neuraminidase inhibitors be used to respond to H5N1
outbreaks unless neuraminidase inhibitors are not available or local
surveillance data show that the H5N1 virus is known or likely to be
susceptible to the adamantanes. A high proportion of H5N1 strains
circulating in Indonesia, Thailand, and Vietnam have been resistant to
adamantanes. Like adamantanes, the effectiveness of neuraminidase
inhibitors against potential pandemic strains could also be constrained
by the emergence of antiviral-resistant strains of the virus. In
Vietnam, a study identified H5N1 strains resistant to Tamiflu, a
neuraminidase inhibitor, and a few seasonal influenza viruses--less
than .5 percent--have been resistant to Tamiflu. Another study examined
the effectiveness of Tamiflu and Relenza, another neuraminidase
inhibitor, against H5N1 viruses. The researchers found that there was
little variation in the effectiveness of Relenza against all H5N1
viruses studied but that there was variation in the effectiveness of
Tamiflu. For example, they reported that one group of H5N1 viruses was
15-to 30-fold less sensitive to Tamiflu than was another group of H5N1
viruses.
Weaknesses in International Influenza Surveillance:
According to the U.S. National Strategy for Pandemic Influenza
Implementation Plan, international capacity for influenza surveillance
still has many weaknesses, including limited influenza sample
collection and sharing. Surveillance requires the collection and
sharing of virus samples and the genetic sequencing of these samples
from both infected humans and animals to monitor if and how a strain is
mutating.[Footnote 40] According to WHO, global influenza surveillance
in humans is weak in some parts of the world, particularly in
developing countries. Surveillance systems in many of the countries
where H5N1 influenza is of greatest concern are inadequate,
particularly in rural areas where many cases have occurred. WHO has
noted that to increase the likelihood of successfully forestalling the
onset of a pandemic, surveillance in affected countries needs to
improve, particularly concerning the capacity to detect clusters of
cases closely related in time and place. Such clusters could provide
the first signal that the virus has begun to spread more easily among
humans. If early signals are not identified, the opportunity for
preemptive action will be missed. In addition, some countries
experiencing H5N1 influenza outbreaks (e.g., Indonesia) have at times
not promptly shared human virus samples with the international
community, thus further weakening international surveillance efforts.
Similarly, a surveillance network to monitor influenza in animals faces
weaknesses. Global animal influenza surveillance can help provide early
recognition of viruses with the potential for causing human influenza.
Surveillance in animals may indicate how an influenza virus is
spreading and evolving. WHO has recommended combining the detection of
new outbreaks in animals with active searches for human cases. However,
influenza surveillance in animals has weaknesses. For example,
definitions of what constitutes an outbreak vary between countries and
may be reported as a single infected farm, an affected village, or an
affected province. In addition, only the number of outbreaks may be
reported rather than more specific information. Moreover, animal
disease surveillance is completely lacking in some countries. For
example, Djibouti and Uganda have no capacity to collect, transport,
and diagnose animal influenza samples. Just as with human influenza
samples, there are concerns that animal samples have also not always
been shared promptly, or for every outbreak.
According to WHO, few countries have the necessary expertise and
facilities to diagnose H5N1. This leads to the need for countries
lacking laboratories these facilities to wait until collected samples
of a strain are tested by labs outside the country, possibly delaying
both timely diagnosis and antiviral administration. Therefore,
laboratories must have the necessary information, guidance, and
materials to allow them to recognize, store, and safely transport H5N1
samples to more specialized laboratories in other countries. In a
previous report, we reported, for example, that Indonesia and Nigeria
both had limited capacity to collect, diagnose, or transport influenza
in human samples.[Footnote 41]
Currently, there is not a good way to quickly and easily determine
whether a patient has H5N1 or a more common type of influenza. The
accuracy of clinical diagnosis of influenza on the basis of symptoms
alone is limited because symptoms from illness caused by other
pathogens can overlap considerably with influenza. The amount of time
required to attain results from diagnostic tests varies from minutes to
several days, with accuracy often being the trade-off for rapid
results. Existing point-of-care tests can provide results rapidly and
determine if the patient is infected with seasonal influenza viruses A
or B but cannot identify avian influenza H5N1.[Footnote 42] A viral
culture test can provide specific information on circulating strains
and subtypes of influenza viruses in 2 to 10 days but may require
longer for more detailed analysis. In addition, the need to conduct
viral culture tests in laboratories with enhanced safety levels can
also restrict their usefulness. HHS recommends an H5 polymerase chain
reaction test, which can be done without the specialized laboratory
facilities required by viral culture tests, for the diagnosis of H5N1
influenza. This test is FDA-approved and is used by public health
laboratories throughout the United States and in many parts of the
world.
Limited Support for Clinical Trials:
Limited support for clinical trials could hinder their ability to
improve understanding of the use of antivirals and vaccines against a
pandemic strain. Clinical trials improve the understanding of
effectiveness, timing of administration, duration of treatment, optimal
dosage, safety, and the balance of risks and benefits of antivirals and
vaccines. Improved understanding gained through clinical trials would
assist with updating international guidance on antiviral use. The
current estimates on the effectiveness of antivirals in a pandemic are
largely based on their use in treating and preventing influenza illness
caused by seasonal influenza strains circulating at the times the
studies were performed. However, the viral characteristics of a
pandemic strain may be different. Similarly, clinical trials are an
essential step in vaccine development and are used for testing the
safety and effectiveness of vaccines. For instance, clinical trials
could test for the optimal dosage of vaccines developed against a
potential pandemic strain.[Footnote 43] However, few governments are
assisting vaccine manufacturers with funding and technical support for
clinical trials.
Limited Production, Distribution, and Administration Capacity Could
Constrain the Availability of Antivirals and Vaccines:
The availability of antivirals and vaccines is constrained by limited
production, distribution, and administration. Vaccine manufacturers'
liability concerns might also limit their willingness to manufacture
these drugs and make them available in certain countries.
Constraints on Antiviral and Vaccine Production:
Current antiviral production is inadequate to reach WHO estimates for
the number of antivirals needed to contain a pandemic. While WHO has
not set a target for national antiviral stockpiles, it stated in 2007
that it is unlikely that sufficient quantities of antivirals will be
available in any country at the onset of a pandemic. WHO estimates that
the quantity of antivirals required to forestall a pandemic would be
enough treatment courses for 25 percent of the population.[Footnote 44]
In addition, there would need to be enough preventative courses to last
20 days for the remaining 75 percent of the population in the outbreak
containment zone.[Footnote 45] While Roche, the primary manufacturer of
Tamiflu, has expanded production, it has stated that the demand for
Tamiflu will need to further increase before there are any new
increases in production.
While vaccination is considered to be the best defense against
influenza, it is unlikely that a vaccine targeted to the pandemic
strain will be available in time to forestall the onset of a pandemic.
HHS has reported that 20 to 23 weeks are currently required from the
start of a pandemic to the availability of a well-matched vaccine; WHO
expects that once a pandemic strain emerges, it is likely that it will
spread globally within approximately 3 months.[Footnote 46] Figure 1
shows how WHO, its Collaborating Centres around the world, and
pharmaceutical manufacturers would proceed to develop and produce
vaccines designed to protect against a newly emerged pandemic strain,
and how long it would take for the vaccines to become available.
Figure 1: Pandemic Vaccine Production Timeline:
[See PDF for image]
This figure illustrates the Pandemic Vaccine Production Timeline, as
follows:
Month 1: Pandemic strain emerges in country of origin;
* Detection of outbreak;
* Isolation of virus;
* Shipment to WHO labs.
Month 2: Develop virus reference;
* Development of reference virus by WHO Collaborating Centres.
Month 3: Prepare for production;
* Manufacturers adapt seed virus for mass production;
* Develop reagents.
Month 4: Produce and test vaccines;
* Pandemic has spread worldwide;
* Production begins.
Month 5: Produce and test vaccines;
* First vaccines become available.
Month 6: Produce and test vaccines;
* First vaccines become available.
Month 7: Produce and test vaccines;
* First vaccines become available.
Source: GAO analysis of HHS, IFPMA, and WHO data.
[End of figure]
Some health authorities have suggested that increased seasonal
vaccination could play a limited role in forestalling the emergence of
a pandemic by limiting the opportunities for human and animal influenza
strains to combine and form a pandemic strain, but it is likely that
the limited availability of seasonal vaccination would limit its role
in forestalling an influenza pandemic. Seasonal vaccine would not
prevent individuals from becoming infected with animal influenza.
However, in the case of an H5N1 strain, promoting seasonal vaccination
prior to the emergence of a pandemic strain, particularly among health
care workers and others in contact with human cases of H5N1 infection
and infected poultry, could reduce the likelihood of H5N1 and seasonal
influenza coinfection in humans.[Footnote 47] Experts fear that such co-
infection could lead to the emergence of a reassorted influenza strain
that has the transmissibility of the human seasonal strain and the
virulence of the H5N1 strain, thus resulting in a pandemic. However,
large-scale global seasonal influenza vaccination would be difficult to
implement because of the lack of influenza vaccination programs in many
countries. Additionally, seasonal vaccination of humans would not
prevent influenza reassortment within animals.
According to WHO, current annual global production capacity for
trivalent seasonal vaccines is approximately 565 million doses; these
doses would only be enough to vaccinate about 9 percent of the world's
population of 6.6 billion people.[Footnote 48] WHO has also stated that
the current demand for and supply of seasonal influenza vaccine is
approximately equal. Thus, without additional production, either by
current manufacturers scaling up their production or by increasing the
number of manufacturers, the supply of seasonal vaccine would not be
able to meet the increased demand that would stem from the promotion of
seasonal vaccination. In fact, due to limitations in vaccine production
capacity, even countries with existing seasonal vaccine programs have
experienced shortages. For example, the United States experienced
vaccine shortages as recently as the 2004-2005 influenza season due to
production problems experienced by one manufacturer.[Footnote 49]
This limited vaccine production capacity would also limit the
availability of a pandemic vaccine in the event of a pandemic since the
processes used to manufacture seasonal and pandemic vaccines are
similar and the manufacturing would take place in the same facilities.
If a monovalent vaccine (that is, a vaccine that contains only one
influenza strain) were produced for a pandemic strain, experts estimate
that approximately three times the number of trivalent doses could be
produced. Consequently, if annual production capacity is sufficient to
produce 565 million doses of trivalent vaccine, 1.695 billion doses of
monovalent vaccine could be produced each year. However, the actual
number of doses that could be produced would depend on a number of
factors including how well the virus strain grows in eggs and the
dosage required. For instance, if a dose larger than 15 micrograms--the
dose required for current seasonal vaccine--was needed, fewer doses
could be produced. Testing on a sanofi pasteur H5N1 vaccine approved by
FDA in April 2007 indicates that a single 15 microgram dose would not
be sufficient to confer immunity. Instead, the testing indicated that
45 percent of individuals who received two 90 microgram doses of this
vaccine--or twelve times as much--developed an immune response expected
to reduce the risk of getting influenza. If this dosage were required
during a pandemic, instead of having the capability to vaccinate 1.695
billion people, only 141,250,000 (one-twelfth as many) could be
vaccinated. This would likely be well below global demand, given a
global population of 6.6 billion people.
The location of vaccine manufacturing facilities could also limit the
role that vaccines would play in forestalling an influenza pandemic.
Experts fear that the concentration in a few countries of vaccine
production capacity could, in the event of a pandemic, lead to vaccine
shortages in countries without domestic manufacturing capacity.
According to WHO, 90 percent of vaccine production capacity is
concentrated in Europe and North America.[Footnote 50] Currently, only
one manufacturer's entire seasonal influenza vaccine production
facilities are located completely within the United States. There is
concern among experts that countries without domestic manufacturing
capacity would not have access to vaccines in the event of a pandemic
if the countries with domestic manufacturing capacity prohibited the
export of vaccine until their own needs were met. Many countries
experiencing H5N1 influenza outbreaks, such as Cambodia and Indonesia,
do not have domestic manufacturers that produce influenza vaccines, and
according to WHO, would require financial and technical support from
the international community to create a domestic pharmaceutical
infrastructure.[Footnote 51]
Constraints on Distribution and Administration:
Limited global, national, and local-level distribution and
administration capacity could restrict the availability of antivirals
at the site of outbreaks for use in forestalling the onset of a
pandemic. Distribution and administration capacities require plans,
delivery networks, facilities suitable for administering the drugs,
trained personnel, and funding to get antivirals to where they are
needed and administer them promptly. As discussed earlier, experience
with seasonal influenza indicates that antivirals are most effective in
treating influenza if they are taken within 48 hours of the onset of
symptoms. This requires an efficient distribution network to get the
drugs to where they are needed.
Antiviral distribution networks are poor or nonexistent in some
countries. We previously reported that as of October/November 2005, 10
of 17 countries reviewed did not have distribution plans for the
release of antiviral stockpiles and there was insufficient information
available to reach conclusions for 4 others.[Footnote 52] Studies of
national pandemic preparedness plans in Europe and the Asia-Pacific
region found that most did not adequately address how antivirals would
be transported to locations where they are needed and how they would be
administered to individuals.[Footnote 53] Thirteen of the 21 European
plans had guidance on priority groups for treatment with antivirals,
but none described the process by which individuals belonging to
priority groups would be identified.[Footnote 54] Most of the plans in
Asian-Pacific countries did not identify such priority groups. The
timely administration of antivirals would also likely be constrained if
there is a scarcity of trained professionals as well as packaging and
instructions that are printed in languages foreign to those
administering the drugs. In addition, countries that depend upon
outside sources to provide antivirals might not have these drugs
available in time to contain an outbreak. Many countries do not have
national stockpiles of antivirals and are dependent on outside sources
to provide these drugs for distribution in the event of an outbreak.
Antiviral stockpiling is expensive, and it may not be feasible for many
countries to establish their own national stockpiles.
Similarly, the availability of vaccines could be affected by
limitations in countries' capacity for distributing and administering
vaccines. For example, a lack of supplementary medical supplies (such
as syringes) could impede the administration of vaccines. Countries'
experience with seasonal vaccination programs indicates potential
problems in the event of a pandemic. IFPMA has noted that many
developing countries have insufficient health care systems to deliver
vaccines. Most countries have little seasonal influenza vaccine
distribution infrastructure and lack financial and human resources to
implement national seasonal influenza vaccination programs. In 2005,
WHO reported that about 50 of the 193 countries in the world, mainly
those that are industrialized and some countries in rapid economic
development, offer influenza vaccination to nationally defined high-
risk groups.[Footnote 55] However, even in industrialized nations such
as the United States, vaccine distribution and administration issues
arise. For example, during the vaccine shortage in the 2004-2005
influenza season, CDC developed a plan to allocate the available
vaccine among states. However, the formula for allocating each state's
allocation was imperfect, resulting in some states having more vaccine
than needed to cover demand and other states having too
little.[Footnote 56]
Manufacturers' Liability Concerns:
Manufacturers' concerns regarding product liability in individual
countries could also hinder the global availability of vaccines.
Experts and vaccine manufacturers have said that the lack of liability
protection increases liability concerns for manufacturers, which may
hinder their willingness to manufacture and distribute vaccines in
countries where they might be held liable for any adverse effects that
occurred from their administration. Concerns regarding potential
liability for the vaccines could hinder efforts by WHO to get companies
to donate vaccines to countries where they are not licensed.[Footnote
57] Industry representatives have stated that manufacturers would need
advance assurance that governments would provide liability protection.
U.S. Government and International Partners' Efforts Are Under Way to
Address Constraints on Use of Antivirals and Vaccines, but Certain
Efforts Face Limitations:
The United States, its international partners, and the pharmaceutical
industry are investing substantial resources in efforts to address the
uncertain effectiveness and limited availability of antivirals and
vaccines. Efforts to make effective antivirals and vaccines more
available include (1) improving disease surveillance on an
international scale in order to monitor the evolution of influenza
strains and the effectiveness of antivirals and vaccines against those
strains, (2) increasing global demand for antivirals and vaccines to
encourage production and spur research and development, and (3)
increasing global distribution and administration capacity. However,
some of these efforts face funding and logistical limitations and will
take several years to complete.
Efforts Are Under Way to Improve Surveillance in Order to Increase the
Effectiveness of Antivirals and Vaccines:
The U.S. government and its international partners are supporting
efforts to increase the effectiveness of antivirals and vaccines by
improving influenza surveillance. International surveillance is
required for monitoring strain evolution in humans and animals to
detect the emergence of new influenza strains and evaluate the
continued effectiveness of antivirals and vaccines as the virus
evolves. Governments, international organizations, manufacturers, and
scientists have initiatives under way to improve international
surveillance by improving disease surveillance in humans, creating
animal surveillance networks, improving animal and human sample sharing
and analysis, increasing international collaboration in monitoring
influenza strains, and improving diagnostic capabilities.
WHO's revised International Health Regulations seek to improve
worldwide disease surveillance in humans.[Footnote 58] The revised
Regulations were adopted in May 2005 and effective on June 15,
2007,[Footnote 59] require that member states report all events that
constitute a public health emergency of international concern, such as
those caused by new and reemerging diseases with epidemic potential
like H5N1 influenza.[Footnote 60] The Regulations set out the basic
public health capacities a country must develop, strengthen, and
maintain to detect, report, and respond to public health risks and
potential public health emergencies of international concern. For
example, at the national level a country is required to be able to
assess all reports of urgent events within 48 hours. Each country must
assess its ability to meet the core surveillance capacities by June
2009 and has until June 2012 to develop these capacities.[Footnote 61]
Among activities to improve influenza surveillance in animals, in May
2005 the World Organisation for Animal Health (OIE) and the Food and
Agriculture Organization of the United Nations (FAO) created the OIE/
FAO Network of Expertise on Avian Influenza (OFFLU), an international
veterinary counterpart to WHO's human Global Influenza Surveillance
Network.[Footnote 62] OFFLU supports international efforts to monitor
and control H5N1 in poultry and other bird species through the
collection and sharing of influenza virus samples from infected
animals. Increased animal surveillance could speed the diagnosis and
reporting of novel influenza strains. One of OFFLU's goals is to put
influenza sequences in the public domain for the benefit of research
and development, and OFFLU is actively supported in this endeavor by
the U.S. government.[Footnote 63] Influenza sequencing reveals complete
genetic blueprints of influenza viruses, information which is used to
develop vaccines and to monitor the emergence of antiviral-resistant
influenza strains. Additionally, sequencing provides information that
might indicate that a virus has changed in such a way to become more
transmissible among humans. OFFLU collects animal influenza samples and
shares them with NIH for sequencing and with CDC for antigenic
analysis.[Footnote 64] NIH sequences the samples and funds the costs of
sequencing these samples. NIH then makes the completed sequences
available in the public domain. Through its Influenza Genome Sequencing
project, NIH makes available to the entire scientific community over
the Internet the genetic sequences of human and animal influenza
viruses. As of December 13, 2007, 2,807 human and animal influenza
viruses have been completely sequenced. In addition to this project,
CDC and NIH have provided materials to countries affected by H5N1 to
test animal influenza virus strains. In the event of a pandemic, CDC
and NIH have also offered them assistance in sequencing influenza
viruses.
An additional effort to improve surveillance through sample sharing is
the Global Initiative on Sharing Avian Influenza Data, formed in August
2006 by a group of scientists from over 40 countries. Genetic sequence
data collected through this initiative will be deposited in a publicly
available database and then after a specified period of time will be
released automatically to publicly funded databases participating in
the International Sequence Database Collaboration or in other publicly
available databases. This initiative will work to overcome restrictions
which have previously prevented influenza information sharing, with the
hope that more shared information will help researchers understand how
viruses spread, evolve, and can potentially lead to a pandemic. This
initiative is open to all scientists, provided they agree to share
their own data, credit the use of others' data, analyze findings
jointly, and publish results collaboratively.
In addition to OFFLU, a surveillance system for animal diseases that
are transmissible to humans has also been established and many
countries have improved their surveillance of animal diseases. FAO,
OIE, and WHO launched the Global Early Warning and Response System for
Major Animal Diseases, including Zoonoses (GLEWS) in July 2006 to
improve the early warning and response capacity of the three
organizations to animal diseases, including those that can spread to
humans.[Footnote 65] GLEWS is the first joint early warning and
response system conceived with the aim of predicting and responding to
such diseases. WHO has stated that from a public health perspective,
early warnings of animal outbreaks that have a known potential to
spread to humans will enable the initiation of control measures that
can prevent human morbidity and mortality. The United Nations System
Influenza Coordinator and the World Bank have reported that many
countries have improved their animal disease surveillance systems. They
noted that better disease surveillance systems, along with improved
laboratory capacity and increased access to epidemiological expertise,
account for improved detection of H5N1 and other influenza viruses.
In April 2007, NIH announced that it was awarding $23 million per year
for 7 years to establish six Centers of Excellence for Influenza
Research and Surveillance. The mission of the centers is to expand
NIH's influenza research program, both in the United States and
internationally, to determine how these viruses cause disease as well
as how the human immune system responds to them. Specific activities
include expanding animal influenza surveillance and studying how
pandemic viruses emerge.
Governments, including the U.S. government, and manufacturers are
undertaking efforts to increase international collaboration to monitor
the evolution of influenza strains. Through a collaborative global
network, CDC's WHO Collaborating Centre is monitoring the H5N1 virus to
track its geographic spread and to identify and analyze changes in the
virus. CDC is providing funds for the shipment of influenza samples to
WHO Collaborating Centres for analysis. As part of its surveillance
role, CDC conducts antiviral susceptibility testing on seasonal and
novel influenza viruses and has been able to identify changes in the
sequence of H5N1 virus samples that could affect their susceptibility
to existing antiviral medications. For example, in January 2007 CDC
testing found an H5N1 virus sample from Egypt with reduced
susceptibility to Tamiflu. FDA, CDC and other WHO Collaborating
Centres, other WHO laboratories, and national regulatory authorities
have also used information on H5N1 strain evolution to recommend
representative strains for use in the development of pre-pandemic
vaccines and to develop H5N1 reference viruses which are shared with
manufacturers. Manufacturers are also supporting the independent
Neuraminidase Inhibitor Susceptibility Network, which includes
government officials and works in collaboration with WHO to monitor
influenza viruses for any signs of strains that have developed
resistance to this class of antivirals.
Concerns regarding the failure of certain countries to share human and
animal influenza samples and the availability of vaccines developed
from these samples have led to efforts to promote sample sharing. In
February 2007, Indonesia announced that it would no longer share H5N1
samples with WHO because the resulting vaccines produced by private
companies were unlikely to be available to developing countries such as
Indonesia. At times, the Indonesian government has also expressed a
desire for royalties from any invention derived from an influenza
sample isolated within its borders. In March 2007, WHO said that an
agreement had been reached and that Indonesia would resume sharing H5N1
samples immediately. However, sample sharing did not resume until May
2007 when, at the World Health Assembly meeting, 17 developing
countries introduced a resolution demanding equitable access to
vaccines made from H5N1 samples the countries provide.[Footnote 66] At
that time, Indonesia provided three samples from two patients to WHO.
Later at that meeting, the World Health Assembly requested that WHO
formulate mechanisms and guidelines aimed at ensuring the fair and
equitable distribution of pandemic influenza vaccines at affordable
prices in the event of a pandemic. Following this, in June 2007 the
health ministers of the Asia-Pacific Economic Cooperation stated they
planned to share influenza virus specimens in a timely manner.[Footnote
67] However, HHS officials told us that concerns remain. In July 2007,
HHS reported to us that Indonesia had not shared any seasonal or H5N1
influenza samples since those it sent to WHO in May 2007. HHS also
noted that the Asia-Pacific Economic Cooperation agreement is not being
followed. A WHO official has also expressed concern. In August 2007, he
stated that by not sharing virus samples, Indonesia is endangering the
world's health as well as its own. Also in August 2007, Indonesian
health officials stated that the county will continue to withhold H5N1
samples at least until a new virus-sharing agreement is developed at an
international meeting in November 2007.[Footnote 68] Later in August
Indonesia sent two samples to CDC for testing, although concerns remain
whether Indonesia will share or continue to withhold samples in the
future. At the November 2007 meeting, no agreement on sample sharing
was reached. Indonesia advocated an accord stating that for every virus
sample sent out of a country, there should be an agreement specifying
that the sample be used only for diagnostic purposes. Commercial use of
the virus would require permission of the country that provided the
sample.
Improved understanding of influenza viruses could improve surveillance
and, in turn, vaccine development. Scientists at NIH, along with a
collaborator at Emory University, have identified mutations that would
help a strain of the H5N1 virus spread easily from person-to-person.
This knowledge could contribute to better surveillance of naturally
occurring influenza outbreaks because efforts could be focused on
identifying viruses with mutations that lead to increased
transmissibility among humans. This could permit the development of
vaccines prior to a pandemic, and possibly help contain a pandemic at
its outset.
WHO and CDC are undertaking a number of activities in order to improve
diagnostic capability worldwide. WHO reported providing equipment and
training to staff working within national laboratories and is providing
experts to give hands-on support. At the regional level, it reported
enhancing the laboratory network with the facilities and expertise to
analyze H5 samples so that every country has access to a regional H5
laboratory.[Footnote 69] This H5 laboratory network has provided
support to countries in shipping samples and providing confirmation of
suspected H5N1cases. According to WHO, four laboratories in Africa have
been upgraded so that they can conduct H5 diagnosis. For the long term,
WHO is working to build and strengthen local H5 diagnostic capability.
In addition, CDC officials stated that among its activities the agency
provides financial and technical assistance to 35 countries, WHO, and
WHO regional offices in order to improve influenza laboratory
diagnostic capability. CDC is also providing training for laboratory
workers and epidemiologists in order to expand laboratory diagnostic
capabilities and develop rapid response teams that could quickly
detect, report, and control outbreaks caused by novel influenza
viruses. CDC officials have also provided laboratory support and
diagnostic reagents to countries investigating H5N1 outbreaks.
Research is being conducted to improve rapid, diagnostic tests for
influenza. In order to forestall a pandemic, it is critical to be able
to identify people with H5N1 quickly. A reliable, rapid diagnostic test
is needed for epidemiological assessments, traveler screening, and
clinical care. Currently, rapid tests cannot distinguish between
strains and subtypes of influenza viruses. To address this shortcoming,
in December 2006, CDC awarded four companies a total of $11.4 million
in contracts to develop new viral diagnostic tests with quicker and
more reliable results that could be used at, for example, a patient's
bedside or a port of entry (see table 3). CDC hopes for FDA approval
and commercialization of these products in 2 to 3 years. In addition,
tests designed for large reference and public health laboratories are
also being developed.[Footnote 70] In February 2006, FDA approved a
test developed by CDC that identifies H5 but not the strain within 4
hours once testing begins. Previously, it would have taken 2 to 3 days.
If the virus is identified as H5, tests are then conducted to identify
the strain. FDA has shared this technology with WHO and its
Collaborating Centres.
Table 3: HHS Contracts Awarded to Companies in December 2006 to Develop
Rapid Diagnostic Tests for Influenza:
Recipient: Cepheid;
Amount (dollars in millions): $2.4.
Recipient: Iquum[A];
Amount (dollars in millions): 3.8.
Recipient: MesoScale;
Amount (dollars in millions): .7.
Recipient: Nanogen;
Amount (dollars in millions): 4.5.
Recipient: Total;
Amount (dollars in millions): $11.4.
Source: CDC.
[A] According to HHS, the Iquum contract was terminated in May 2007 due
to technical issues.
[End of table]
Research is also under way to improve other types of diagnostic tests
for influenza. For example, using funding from NIH, scientists at the
University of Colorado at Boulder and CDC have developed a test that is
based on a single influenza virus gene that could allow scientists to
quickly identify influenza viruses, including H5N1. This test offers
several advantages over available tests including being based on a gene
that, unlike hemagglutinin and neuraminidase, does not mutate
constantly. Consequently, the researchers believe that this test will
be more useful than other tests because it will provide accurate
results even if the hemagglutinin and neuraminidase genes mutate.
However, WHO has cautioned that the availability of such tests are at
least 4 years away.
Efforts Are Under Way to Increase Demand for Antivirals and Vaccines to
Encourage Production and Spur Research and Development:
Efforts to expand seasonal vaccination and build national stockpiles of
antivirals and pre-pandemic vaccines are under way to encourage
increased demand for these drugs. Demand for seasonal influenza
treatment drives global production capacity for antivirals and all
types of influenza vaccines. Increasing demand through government
support provides incentives for manufacturers to develop more effective
antivirals and vaccines.
Efforts to Increase Demand to Encourage Production:
While the primary benefit of increased seasonal vaccination would be
the enhanced protection against seasonal influenza, WHO has stated that
increased demand for seasonal vaccines would spur manufacturers to
increase their vaccine manufacturing capacity. One of WHO's goals is to
increase seasonal vaccine coverage in countries that already use
seasonal vaccine to 75 percent of target populations by 2010, which
would require an increase in global vaccine production to 560 million
doses to cover use in these countries only.[Footnote 71] Some countries
with seasonal influenza vaccination programs had increased their use of
seasonal vaccines prior to WHO setting vaccination goals, thus
providing incentives for manufacturers to increase overall vaccine
production capacity. In October 2007, WHO stated that seasonal
influenza vaccine capacity is expected to rise to 1 billion doses
annually in 2010, provided sufficient demand exists.
Increased demand for antivirals and pre-pandemic vaccines also stems
from orders placed by countries to build national stockpiles. According
to Roche, as of April 2007, more than 80 countries had ordered Tamiflu
for their own national antiviral stockpiles. Some countries, including
Australia, France, and the United States, are also ordering Relenza to
supplement their Tamiflu stockpiles. The United States had 36.6 million
neuraminidase treatment courses in its federal stockpiles as of August
6, 2007, consisting of 30.8 million treatment courses of Tamiflu and
5.8 million treatment courses of Relenza. It also had 3.6 million
treatment courses of rimantadine, an adamantane, on-hand for a total
stockpile of 40.2 million antiviral treatment courses. Approximately
100,000 additional Tamiflu treatment courses and 700,000 additional
Relenza treatment courses are currently on order for the stockpile. The
U.S. goal at the national level is to have a federal stockpile of 50
million antiviral treatment courses. In addition, states and other
entities had stockpiles totaling 12.9 million treatment courses of
Tamiflu and 1.6 million treatment courses of Relenza as of August 6,
2007. Similarly, Australia, Japan, the United States, and countries in
Europe have been establishing stockpiles of pre-pandemic vaccines. For
example, in 2005, sanofi pasteur agreed to produce 1.4 million doses of
H5N1 pre-pandemic vaccine for France's stockpile. It is also providing
H5N1 pre-pandemic vaccines for national stockpiling in the United
States and Italy. In addition, GlaxoSmithKline Biologicals and Novartis
Vaccines and Diagnostics are also producing H5N1 pre-pandemic vaccine
for the U.S. national stockpile. The United States has stockpiled
enough H5N1 pre-pandemic vaccine to cover about 7 million people. The
United States' goal is to have a pre-pandemic vaccine stockpile of
treatment courses for 20 million persons.[Footnote 72] However,
developing countries may not be able to build such antiviral and
vaccine stockpiles.
Antiviral manufacturers have expanded their production capabilities.
Roche expanded its Tamiflu production so that it could produce 400
million treatment courses of Tamiflu by the end of 2006. Roche noted
that this represents an approximate 15 fold increase over its
production capacity of 27 million treatment courses in 2004. In April
2007, Roche stated that its production capacity now exceeded government
and corporate orders for Tamiflu received to date.[Footnote 73] To
increase capacity, Roche expanded production from one facility to eight
Roche sites, including the United States where 80 million Tamiflu
treatment courses can now be produced. In addition, Roche now has 19
external manufacturing partners that perform particular functions in
the manufacturing process. Roche has also granted sublicenses to
selected drug companies in China and India to allow them to produce
Tamiflu in its generic form, oseltamivir, which will increase the
amount of that antiviral available globally. In Africa, Roche granted a
sublicense to a South African company allowing it to produce
oseltamivir to increase production and speed up availability of the
drug for use against a pandemic strain in Africa.[Footnote 74]
GlaxoSmithKline, the manufacturer of Relenza, is undertaking efforts to
boost Relenza production. While less than 1 million treatment courses
of Relenza were produced in 2005, GlaxoSmithKline stated in May 2006
that it planned to increase production capacity in its existing
facilities in North America, Europe, and Australia. It increased
production to 15 million treatment courses in 2006 and plans to produce
40 million treatment courses in 2007. GlaxoSmithKline also stated that
it is willing to license other manufacturers to produce Relenza in its
generic form, zanamivir. In September 2006, GlaxoSmithKline announced a
licensing agreement with a Chinese drug company to produce the
antiviral and sell it in China, Indonesia, Thailand, Vietnam, and other
developing countries.
Governments and manufacturers are also working to increase the global
production of vaccines by helping to build production facilities and
supplying the technology and resources necessary to produce influenza
vaccines. In September 2006, WHO stated that worldwide vaccine
production capacity is expected to increase by 280 million trivalent
doses in the next 2 to 3 years.
* The U.S. government has offered assistance to countries trying to
create the infrastructure necessary for vaccine production. For
example, HHS has provided countries with reagents, the chemicals
required to assess vaccine effectiveness, and training for testing
vaccines. It also works with countries to help them develop their own
reagents and tests for use in clinical trials and other research.
* WHO's Global pandemic influenza action plan to increase vaccine
supply, dated September 2006, proposes building new production plants
in both developing and industrialized countries as one means to
increase production capacity.[Footnote 75]
* In October 2006, HHS announced a grant of $10 million to WHO to
support influenza vaccine development and manufacturing infrastructure
in other countries, while Japan has contributed $8 million. In April
2007, WHO announced that it was awarding grants to six countries to
help them develop the capacity to make influenza vaccine.[Footnote 76]
Two of the projects will be in Latin America and four in Asia. Three of
the Asian countries receiving grants--Indonesia, Thailand, and Vietnam-
-have had cases of persons infected with H5N1 influenza. Manufacturers
have also committed substantial funds to increase their own vaccine
production capacity.[Footnote 77]
* Additionally, sanofi pasteur signed a technology transfer arrangement
with the governments of Thailand, Mexico, and Brazil.
* In June 2007, HHS awarded a $77.4 million contract to sanofi pasteur
and a $55.1 million contract to MedImmune to renovate existing vaccine
manufacturing facilities in the United States and to provide warm-base
operations for manufacturing pandemic influenza vaccines. In warm-base
operations, a facility does not shut down. HHS stated that these
changes will increase production capacity and permit year-round
production of pre-pandemic influenza vaccines for the national
stockpile, which is currently limited to 3 months per year.
* In July 2007, sanofi pasteur announced that it had completed
construction of a new influenza vaccine manufacturing facility in the
United States. It also noted that it was expanding its influenza
vaccine manufacturing capacity in France.
Encouraging Further Research and Development:
Increased demand through government support has provided incentives for
manufacturers to develop more effective antivirals and vaccines.
Manufacturers are conducting research on new antivirals and on
improving the use of existing antivirals. Manufacturers are also
working to improve the effectiveness of vaccines to combat pandemic
influenza through such activities as developing pre-pandemic vaccines,
examining cell-based production technology, studying substances that
can be added to vaccines to improve effectiveness, and conducting
research on vaccines that would provide protection against multiple
influenza strains. These studies could be used to help define
additional studies and resources that might be needed to assess the
safety, effectiveness, and risk and benefit of products, and
appropriate use of proposed new products or new uses of existing
products.
Research on and Development of Antivirals:
Development of new antivirals is particularly important due to concern
over the emergence of antiviral-resistant influenza strains that could
render existing antivirals ineffective. Manufacturers are developing
and testing new antivirals, and the U.S. government is providing
support to manufacturers that are developing new antivirals. In 2005,
HHS announced plans to spend $400 million to develop new antiviral
drugs. In January 2007, HHS awarded a 4-year $103 million contract to
BioCryst Pharmaceuticals, Inc., to support development of a new
antiviral, peramivir.[Footnote 78] Sankyo Co., Ltd., of Japan and Biota
Holdings Limited of Australia are working together to develop new
antivirals called long-acting neuraminidase inhibitors. These companies
have received a $5.6 million grant from HHS to accelerate the
development of these antivirals.
In addition to developing new antivirals, governments and manufacturers
are exploring ways in which existing antivirals could be used to treat
influenza more effectively and efficiently. For example, researchers
are examining the potential use of antiviral combination therapy, which
would entail the use of more than one antiviral to treat an influenza
infection. Combination antiviral therapy may be more effective and
could reduce the likelihood that an antiviral-resistant strain might
emerge because, for example, there may be less chance that a strain
resistant to both antivirals would emerge. Researchers are also
examining the use of antivirals with other types of pharmaceuticals.
NIH, the Department of Defense, and the Department of Veterans Affairs
are collaborating on a study to determine if Tamiflu used in
combination with the drug probenecid can stretch the supply of
Tamiflu.[Footnote 79] The aim of these studies is to determine whether
the combination of these drugs results in Tamiflu remaining in the body
longer, thus reducing the amount of Tamiflu that an individual would
need to take and effectively increasing the supply of the drug. NIH has
also provided funding to the South East Asian Influenza Clinical
Research Network, to improve understanding and clinical management of
influenza through clinical research, as well as to increase clinical
research capacity in participating countries (Indonesia, Thailand, and
Vietnam). One ongoing study will compare the safety and effectiveness
of standard-and high-dose Tamiflu in treating animal and severe
seasonal influenza in hospitalized children and adults. Planned studies
include the evaluation of the safety and tolerability of the long-term
use of Tamiflu and Relenza to prevent influenza in health care workers
and a study of the safety and effectiveness of using intravenous
Relenza for the treatment of H5N1 infection in adults and children.
Research on and Development of Pre-Pandemic Vaccines:
Manufacturers, sometimes with the assistance of governments, are
working to develop pre-pandemic vaccines. These vaccines might provide
some protection against a pandemic strain and also give manufacturers
experience in producing effective vaccines for a potential pandemic
strain. The United States has been the primary government sponsor of
these efforts although other countries have sponsored some studies;
other studies have been conducted without government support. The
United States has supported studies of vaccines developed by Baxter
International, Inc., MedImmune, Novartis, and sanofi pasteur.
WHO has reported two ways in which a pre-pandemic vaccine could be
used. First, such a vaccine could be used to protect selected
populations at risk of being infected by viruses currently circulating
among poultry. Second, it could be used to immunize general populations
or selected groups (e.g., health care workers) against a potential
pandemic strain. However, WHO points out that the pandemic virus may be
quite different than what people are immunized against and therefore
the pre-pandemic vaccine may not be protective.
Pre-pandemic vaccine might also be used as part of a "prime-boost"
series in which two doses of vaccine based on different strains would
be given. The first vaccine would be a pre-pandemic vaccine that would
prime the immune system for a second vaccine. The second vaccine would
match the pandemic strain. It is hoped that together the two doses
would result in immunity. However, the data needed to support such an
approach have not been fully developed.
In April 2007, FDA licensed the first pre-pandemic vaccine for human
use in the United States against H5N1 based on the results of a
clinical trial conducted by NIH, although the results revealed
limitations. FDA approved the vaccine for the immunization of persons
18 to 64 years of age at increased risk of exposure to the H5N1
influenza subtype. The vaccine, manufactured by sanofi pasteur, will
not be marketed commercially. Instead, the vaccine has been purchased
by the federal government for inclusion in the United States stockpile
for distribution if needed.[Footnote 80] However, NIH's clinical trial
showed limitations of the vaccine. First, in previously unexposed
populations, two 90 microgram doses are needed to elicit the levels of
immune responses usually thought to be adequate to provide protection
instead of the single 15 microgram dose of seasonal influenza vaccine
that is needed for protection against a seasonal influenza strain.
Second, even with this larger dosing regimen, vaccination results in an
immune response thought to be protective in only 45 percent of those
receiving the vaccine. Studies of seasonal vaccines in healthy persons
have demonstrated that effectiveness against well-matched strains is 70
to 90 percent.[Footnote 81] In addition, experts have noted that such a
high vaccine dose could result in an unusually high rate of adverse
reactions. NIH, along with other federal agencies, sanofi pasteur, and
other manufacturers, continue to work on the development of vaccines
that will stimulate enhanced immune response at lower doses of vaccine.
GlaxoSmithKline and Novartis have both announced that they have
submitted pre-pandemic H5N1 vaccines for approval in Europe.
Research on and Development of Cell-Based Production Technology:
To speed development and production of new technologies for influenza
vaccines, the U.S. government and manufacturers are pursuing the
development of cell-based vaccine production technology as an
alternative method to current egg-based production.[Footnote 82] Egg-
based vaccine production cannot be scaled up quickly and egg supplies
can be compromised in the event of an influenza outbreak.[Footnote 83]
According to HHS, cell-based technology could be scaled up quickly
because cells can be frozen in advance and large volumes grown quickly,
thus providing surge capacity in the event of a pandemic. In April
2005, HHS awarded a $97 million 5-year contract to sanofi pasteur for
development of a cell-based influenza vaccine. Subsequently, HHS
awarded more than $1 billion in contracts to accelerate development and
production of cell-based production technologies for influenza vaccines
within the United States. (See table 4.) HHS officials told us that
this funding provided companies with the incentive to invest in this
technology. In the past, companies did not want to invest in cell-based
production technologies because it would not increase efficiency as
both cell-and egg-based production would yield similar amounts of
vaccine. FDA issued draft guidance in September 2006 to assist
manufacturers in developing cell-based vaccines. In other countries,
companies are making similar although smaller investments than in the
United States, usually without government support.
Progress has already been made on the development of cell-based
influenza vaccines. For example, Solvay Pharmaceuticals received
authorization to market its cell-culture influenza vaccine in the
Netherlands in 2001. However, this vaccine has not yet been marketed.
In June 2007, the European Union approved a cell-culture-derived
seasonal influenza vaccine manufactured by Novartis. The company has
stated that it expects to submit an application for approval to market
the vaccine in the United States in 2008.[Footnote 84]
Table 4: HHS Contracts Awarded in May 2006 to Develop Cell-Based
Vaccines:
Recipient[A]: Solvay Pharmaceuticals;
Amount (dollars in millions): $298.59.
Recipient[A]: GlaxoSmithKline Biologicals;
Amount (dollars in millions): 274.75.
Recipient[A]: Novartis Vaccines and Diagnostics;
Amount (dollars in millions): 220.51.
Recipient[A]: MedImmune;
Amount (dollars in millions): 169.46.
Recipient[A]: DynPort Vaccine;
Amount (dollars in millions): 40.97.
Recipient[A]: Total;
Amount (dollars in millions): $1,004.28.
Source: HHS.
[A] In April 2005 HHS awarded a $97 million 5-year contract to sanofi
pasteur to develop a cell-based vaccine.
[End of table]
Research on and Development of Adjuvants:
HHS has awarded contracts to manufacturers to research and develop
influenza vaccines that use adjuvants. An adjuvant is a substance added
to a vaccine to improve its effectiveness so that less vaccine is
needed to provide protection. When added to a vaccine, adjuvants can
stretch the vaccine supply by decreasing the amount of vaccine needed
per person while still providing the same level of protection.
Adjuvants have been used in other vaccines, but not in influenza
vaccines. GlaxoSmithKline, Novartis, and sanofi pasteur have announced
study results that show that adjuvanated influenza vaccines produced
possible protective immunity at lower doses than did nonadjuvanated
vaccines. For example, Novartis has reported that its adjuvanated
vaccine produced a strong immune response against H5N1, H5N3, and H9N2,
but that its vaccine without adjuvant produced a poor response. In
January 2007, HHS announced that it had awarded contracts totaling
$132.5 million to three vaccine manufacturers for the development of
H5N1 vaccines using an adjuvant. (See table 5.)
Table 5: HHS Contracts Awarded in January 2007 to Develop Influenza
Vaccines Containing an Adjuvant:
Recipient: GlaxoSmithKline Biologicals;
Amount (dollars in millions): $63.3.
Recipient: Novartis Vaccines and Diagnostics;
Amount (dollars in millions): 54.8.
Recipient: Iomai Corporation;
Amount (dollars in millions): 14.4[A].
Recipient: Total;
Amount (dollars in millions): $132.5.
Source: HHS.
[A] Iomai Corporation would be eligible to receive an additional $114
million upon successful completion of Phase I trials. Phase I trials
are the first stage of testing new drugs or treatments in people and
normally include a small (less than 100) group of healthy volunteers.
[End of table]
In addition to potentially stretching the vaccine supply, there is
evidence that when adjuvants are added to a vaccine, that vaccine might
also provide protection against strains to which it is not fully
matched. Research by Novartis demonstrated that its H5N3 vaccine
generated a better immune response against H5N1 strains with an
adjuvant than without it. Similarly, a GlaxoSmithKline vaccine with
adjuvant provided protection against two diverse H5N1 influenza strains.
Research on and Development of Universal Vaccines and Other Vaccines
That Protect Against Multiple Influenza Strains:
Current efforts to develop a universal influenza vaccine are intended
to address constraints on both the effectiveness and availability of
vaccines. A universal vaccine would protect against multiple virus
strains.[Footnote 85] Availability of universal influenza vaccines
would eliminate the current process required to reformulate seasonal
influenza vaccines each year. Consequently, if vaccines effective
against pandemic influenza could be available when a pandemic strain
emerged, there would not be a 20-to 23-week period between
identification of the pandemic strain and the ability to produce an
effective vaccine. The recent threat of a human pandemic arising from
H5N1 has spurred new funding for manufacturers currently attempting to
develop universal influenza vaccines. In October 2005, a consortium of
companies and universities announced that it had received a 2-year $1.4
million grant from the European Union to support the Universal Vaccine
project. The aim of this project is to develop an easily-administered
nasal vaccine that provides life-long protection against influenza.
Manufacturers such as Merck and Cytos Biotechnology are also working to
develop a universal vaccine. NIH is working to bring universal vaccine
candidates through the pre-clinical development stage.
Despite the recent increase in funding, experts caution that a
completely universal influenza vaccine is years away.[Footnote 86]
Therefore, some researchers and manufacturers are developing live
attenuated vaccines that might protect against a matched strain as well
as mutated strains that typically emerge from year to year.[Footnote
87] These live attenuated vaccines would not be completely universal,
but are easier to develop than universal vaccines and may provide
broader protection than current vaccines that match a specific
influenza strain. For example, MedImmune's current seasonal FluMist
vaccine, which is a live attenuated vaccine, proved effective in
children against the H3N2 strain to which it was fully matched as well
as against H3N2 strains for which there was a mismatch in studies in
children. However, this may not be the case in adults. Evidence
suggests that a live attenuated vaccine was less effective in
protecting against mismatched strains in healthy adults than was the
inactivated trivalent vaccine. In September 2005, HHS announced that it
would work with MedImmune to develop at least one vaccine for each of
the 16 identified hemagglutinin influenza proteins. According to
experts, it is not clear whether live attenuated virus vaccines matched
only for the hemagglutinin protein (e.g., H5 or H7) would work as well
against a pandemic strain as would a vaccine matched to the particular
strain. However, as in the case of pre-pandemic vaccines, even if
limited in their effect these vaccines might help reduce mortality
during a pandemic while a fully matched vaccine is developed. HHS
officials noted that the protection offered by live attenuated vaccines
against multiple strains of different subtypes has yet to be
established. It has also been noted that even if an acceptable live
attenuated H5N1 vaccine is developed, it could not be used as a pre-
pandemic vaccine. There is concern that it could reassort with a
circulating seasonal influenza virus and thereby increase its
transmissibility among humans.
Similarly, research has been conducted using vaccines made from whole
influenza virus rather than just parts of the virus. Studies from two
vaccine manufacturers, Baxter and Biken, have independently suggested
that whole virus vaccines provide protection against multiple strains
of the H5N1 virus and require a smaller dose than do vaccines made from
parts of the virus. Consequently, the use of whole virus vaccine might
not only increase the number of influenza strains against which one is
protected, but also increase the number of doses available.
To Increase Availability, Governments and International Organizations
Have Worked with Manufacturers to Improve Distribution of and
Administration Capacity for Antivirals and Vaccines:
Increasing global availability of antivirals and vaccines includes
improving the global capacity for their distribution and
administration. These efforts also include establishing global and
regional antiviral stockpiles and addressing restrictions that
different national regulations place on drug manufacture and approval.
WHO, countries, and pharmaceutical manufacturers have established
global and regional antiviral stockpiles to enhance the availability
and quick distribution of antivirals to the site of outbreaks. In
August 2005, Roche donated 3 million treatment courses of Tamiflu to
WHO for a global stockpile to contain or slow the spread of a pandemic
at its origin.[Footnote 88] According to Roche officials, the size of
the stockpile was based on studies that indicated that 3 million
treatment courses would be sufficient to stop the spread of a pandemic
strain at its source. Roche will be responsible for the delivery of
Tamiflu from these stockpiles to the international airport closest to
the outbreak, where it will transfer the Tamiflu to WHO. It will then
be the responsibility of the affected countries to distribute the
donated antivirals within their country to contain outbreaks.
Subsequently, in January 2006 Roche announced the donation of an
additional 2 million treatment courses to WHO for the establishment of
regional stockpiles. In March 2007, WHO stated that these drugs are for
the use of countries currently experiencing human outbreaks of animal
influenza. Supplies from this second donation have already been sent to
those countries. Additionally, some countries have taken the lead in
funding regional stockpiles. Japan has provided 500,000 treatment
courses of Tamiflu for a regional stockpile for Asia. Japan is also
funding the delivery of antivirals from that regional stockpile to the
capitals of affected Asian nations. Discussions are under way for HHS
to assist in this antiviral stockpiling. For example, there are
discussions about sharing antivirals from the United States stockpile,
but these drugs could be recalled for domestic use if outbreaks could
not be contained or if an outbreak occurred in North America. In May
2006, HHS sent a stockpile of approximately 260,000 treatment courses
of Tamiflu to Asia to be pre-positioned for international containment
efforts in the event of a pandemic influenza outbreak in that
region.[Footnote 89]
The United Nations System Influenza Coordinator and the World Bank
reported in December 2007 that individual countries have also purchased
or are planning to purchase antivirals but that coverage in many
countries remains limited. Sixty-eight percent of countries worldwide
have purchased antivirals and an additional 22 percent plan to purchase
them. However, the agencies also note that 36 percent of countries
report that that their supply of antivirals covers less than 1 percent
of their population while another 37 percent report that their
antiviral supply covers from 1 to 20 percent of their populations.
Individual countries and WHO are also establishing pre-pandemic
influenza vaccine stockpiles. Several industrialized countries,
including the United States, have established pre-pandemic influenza
vaccine stockpiles to vaccinate critical workforce and primary health
care workers at the onset of a pandemic. WHO is working to establish a
pre-pandemic vaccine stockpile. Such a stockpile could help to
alleviate developing countries' concerns about their lack of access to
H5N1 vaccines developed using virus samples provided by them. In April
2007, a WHO expert committee wrote that there is sufficient scientific
support for creating a stockpile of H5N1 vaccine for use in countries
without influenza vaccine production capacity or the ability to
purchase stockpiles of H5N1 vaccines. The committee noted that there is
some evidence that current H5N1 vaccines produce a protective immune
response against other H5N1 viruses as well. Following this, in May
2007, the World Health Assembly passed a resolution requesting WHO to
establish an international stockpile of vaccines for H5N1 or other
influenza viruses of pandemic potential. In June 2007, GlaxoSmithKline
announced that it would contribute 50 million doses of its H5N1 vaccine
to the stockpile, enough to vaccinate 25 million people. Also in June,
WHO stated that three additional companies had indicated their
willingness to make some of their H5N1 vaccine available for the
stockpile.
In an effort to facilitate access to various vaccines, FDA and its
international counterparts, in collaboration with WHO, are developing a
standard set of data requirements to support the licensure of pandemic
and pre-pandemic vaccines. Each country has its own requirements for
the development and licensure of vaccines for human use (which include
testing in clinical trials).[Footnote 90] If demand were to surge as
might happen in the event of a pandemic, the time needed to go through
the regulatory process to gain approval for a new vaccine could
constrain its availability.[Footnote 91] FDA and its international
counterparts, in conjunction with WHO, participate in international
working groups that examine regulations for the development and
manufacturing of influenza vaccines.
Some governments are also exploring other avenues to speed up their
domestic regulatory process to enhance pandemic preparedness.
Currently, FDA's goal is to complete the review of a "standard"
application in the United States for vaccine licensure within 10
months. However, the goal for review of a "priority" license
application is 6 months. Priority reviews are given to those vaccines
that have the potential for providing significant preventive,
diagnostic, or therapeutic advancement as compared to existing
treatments for a serious or life-threatening disease. In addition, FDA
has processes intended to shorten the time needed for commercial
development and FDA review in certain circumstances. For example,
because it can take many years to determine whether a drug provides
real improvement for patients--such as living longer or feeling better-
-FDA has a process known as "accelerated approval." Under accelerated
approval, applications are reviewed using a substitute measurement of
effectiveness that is considered likely to predict patient benefit.
Similarly, the European Union is pursuing approval for pre-pandemic
vaccines as a mechanism to expedite approval for a pandemic
vaccine.[Footnote 92] Prior to the onset of a pandemic, these pre-
pandemic vaccines undergo safety and effectiveness testing and are
submitted for approval. In the event of a pandemic, this approved pre-
pandemic vaccine would then be reformulated to match the pandemic virus
and expedited approval for the reformulated vaccine would be sought.
Because the application would only pertain to a variation on the
earlier, approved, pre-pandemic vaccine, regulatory approval is
expected to be faster.[Footnote 93] Both GlaxoSmithKline and Novartis
have had pre-pandemic vaccines approved by the European Union under
this mechanism. In addition, GlaxoSmithKline, Novartis, and sanofi
pasteur have submitted additional vaccines for approval under this
process.
Certain Efforts to Increase the Effectiveness and Availability of
Antivirals and Vaccines Face Limitations and Will Take Several Years:
While efforts are under way to alleviate constraints upon the
effectiveness and availability of antivirals and vaccines, certain
efforts face limitations and will take several years to complete. The
strengthening of animal and human surveillance systems is vital to
increasing the effectiveness of antivirals and vaccines. However,
according to OFFLU officials, that network lacks sufficient funding to
hire staff needed to analyze influenza strains. Officials fear that
without this staff, scientists might not continue to submit samples to
OFFLU--which are analyzed and presented in public databases--out of
concern that they would not be analyzed. FAO, OIE, and WHO have stated
that greater support of OFFLU is required in order for it to fulfill
its functions. Experts have noted that public access to databases that
contain influenza sequence information is vital to understanding the
spread and evolution of influenza viruses and, therefore, to the
research and development of influenza treatments.
International support for clinical trials--necessary for developing and
evaluating the effectiveness of antivirals and vaccines--is largely
provided by only four countries: the United States, Australia, Japan,
and the United Kingdom. The United States supports clinical trials for
antivirals and vaccines being developed by global manufacturers, but
experts state that more widespread and consistent international support
is needed. Clinical trials are also required to test effectiveness and
cross-protection provided by pre-pandemic vaccines. The United States,
Australia, Japan, and the United Kingdom have provided the most support
for pandemic vaccine development. However, only the United States
provides substantial support to both domestic and international
manufacturers for such trials. According to IFPMA representatives, the
United States' efforts are the primary governmental source for funding
clinical trials for these vaccines.
Increasing demand for vaccines is likely to continue to pose
difficulties because a number of countries will still need to balance
concerns about a potential pandemic against other existing public
health concerns. Low demand for vaccines to treat seasonal influenza is
due in part to the low priority placed on seasonal influenza by many
countries. As discussed earlier, current global demand for seasonal
influenza vaccines is lower than global need, which is the amount
required to cover individuals under medical guidelines for influenza
vaccination.[Footnote 94] Manufacturers have been reluctant to invest
in the development and production of vaccines due to this low demand
and disincentives such as low profits. One reason for low demand is
that seasonal influenza programs compete with many other public health
priorities for limited budgets in developing countries. For example,
Indonesia, one of the countries experiencing human H5N1 outbreaks, is
also dealing with other diseases as well as the aftermath of a tsunami,
volcanic eruptions, and earthquakes. Some developing countries are
willing to implement seasonal influenza vaccination programs but
require outside funding to do so. One objective of WHO's Global
pandemic influenza action plan to increase vaccine supply is to
increase seasonal vaccine use. According to WHO, a minimum of $300
million is required to do this.[Footnote 95] Similarly, efforts to
increase vaccine production capacity can also be problematic. Citing
Vietnam as an example, NIH officials told us that countries may have
been too overwhelmed with H5N1 outbreaks to accept offers of assistance
to develop vaccine production infrastructure.
Although efforts are under way to increase antiviral and vaccine
manufacturers' production capacity by building new facilities, these
new facilities are not expected to be ready to produce antivirals and
vaccines for several years. According to manufacturers, it will take at
least 5 years to build new vaccine manufacturing facilities and receive
regulatory approval. WHO stated that it will take the six countries
that received grants to develop vaccine production capacity at least 3
to 5 years to begin producing vaccine. Additionally, Roche granted
sublicenses to selected drug companies in developing countries for the
production of generic versions of Tamiflu. However, these agreements
will not immediately alleviate any shortages due to the complicated
production process for Tamiflu. Roche has estimated that it would take
2 to 3 years for a new facility to produce Tamiflu on a large scale. It
has also stated that, even with all the materials necessary for
production available, it takes 6 to 8 months to produce Tamiflu.
Similarly, GlaxoSmithKline has stated that it would take a minimum of 6
to 9 months to increase production capacity for Relenza. WHO has stated
that it is unlikely that sufficient quantities of antivirals will be
available in any country at the onset of a pandemic. Further, in
November 2006, Roche stated that because of high demand and long
manufacturing lead times for Tamiflu, it is highly unlikely that it
would be able to fill large Tamiflu orders on short notice.
Demonstrating the importance of demand in driving production capacity,
Roche announced in April 2007 that it planned to reduce Tamiflu
production because it now exceeded demand for the drug. Roche officials
stated that if demand were to increase, it would take 4 months to
return the production level to 400 million treatment courses annually.
Although global, regional, and national stockpiles of antivirals are
being established, little progress has been made in improving the
capacity for distributing the stockpiled antivirals to the site of
outbreaks around the world, particularly within developing countries.
According to Asian Development Bank officials, the logistics of
distributing antivirals in the event of a pandemic would be of greater
concern than the limited supply of antivirals. Although the cost and
logistics of transporting antivirals from a stockpile to a country's
capital are addressed to some extent by WHO and those countries and
manufacturers that have donated antivirals, issues of transportation
from the capital to a province or distant region remain unaddressed by
many national governments. WHO has established protocols for countries
to request Tamiflu for containment purposes from its global stockpile.
Roche, the donor of the WHO global stockpile, will deliver the drugs to
the international airport nearest the crisis and hand them over to WHO.
National authorities would then be responsible for the storage,
transportation, and administration of those drugs within their borders.
To do so effectively, governments must have plans in place prior to an
outbreak as well as adequate resources to implement them. The U.S.
government has assisted countries in developing such plans. In June
2007, WHO officials reported that over 178 countries have drafted or
finalized their preparedness plans. However, WHO has noted that not all
plans have incorporated its rapid containment protocol.
Agency Comments and Our Evaluation:
HHS, the Department of State and WHO provided comments on a draft of
this report. The comments from HHS and the Department of State are
reproduced in appendixes I and II. WHO provided comments via e-mail and
stated that the report was comprehensive and useful.
In its comments, HHS said that we had lost the larger context of all
efforts with respect to pandemic preparedness and that HHS's antiviral
and vaccine strategies and implementation plans are not captured.
Expressing concern about our focus on antivirals and vaccines, HHS said
that these are only one piece of the agency's broader scope of work on
this topic. It cautioned that the use of antivirals and vaccines in
response to a pandemic is part of a larger, integrated whole, so
viewing them outside of the broader context is likely to raise other
questions and issues. HHS said that we were assuming that antivirals
and vaccines are the only tools necessary to forestall a pandemic. HHS
commented on the uncertainty of success associated with measures such
as stockpiling antivirals, stating that one must not assume that
establishing antiviral stockpiles has solved the problem. HHS noted
that if a potential pandemic is identified early, efforts at
containment should and will be attempted. It further commented that if
containment fails, the effort may still have the effect of slowing the
pandemic's rate of spread while if it succeeds, a pandemic may be at
least temporarily averted. In its comments, HHS stated that as a
preventive health measure only a vaccine will have the capability of
dramatically changing the course of an influenza pandemic.
We do not agree that we have lost the larger context of efforts to
prepare for a pandemic. This work was done in response to a
congressional request that we study the role that antivirals and
vaccines could play in forestalling a pandemic. While this was the
focus of this engagement specifically, we are well aware that
antivirals and vaccines are just two of many possible measures that
could be taken in response to an influenza pandemic. As HHS notes in
its comments, we have issued other reports on various aspects of
pandemic preparedness (see the Related GAO Products section of this
report) and we have ongoing work on numerous other aspects of this
issue. We stated on page 2 of the draft report provided to HHS for
comment that antivirals and vaccines may play a role in forestalling a
pandemic, but we did not suggest that they were the only available
response measures. Nonetheless we have added language to the report to
make it clearer still that antivirals and vaccines are just two of a
variety of available countermeasures that are being contemplated by
WHO, HHS, and other agencies charged with the responsibility of
protecting the public in the event of a pandemic. However, a discussion
of the full range of possible responses to an influenza pandemic
currently being contemplated by HHS and other organizations and
agencies is beyond the scope of this report.
HHS also expressed concern with our discussion of "forestalling" a
pandemic, suggesting that the premise that a pandemic can be
forestalled is not one widely held by the public health or scientific
community and is misguided and misleading. They said that few believe
that a developing pandemic can be stopped in its tracks. In elaborating
on this point, HHS suggested that the concept that antivirals and
possibly vaccines might be used to stop an incipient pandemic or to
slow the spread should be explicitly stated instead of using the word
forestalled in a way that is very likely to be misinterpreted. They
note that theoretically, the only way to truly forestall a human
pandemic would be to eliminate the avian reservoir from which a future
pandemic is likely to emerge.
In the draft of this report provided to HHS for comment, we defined the
word "forestalling" to mean "preventing or at least delaying." We use
this term to suggest that, while preventing a pandemic would be the
desired result of any response effort, delaying the pandemic would
perhaps be the more likely yet still desired result. It is not clear
why the level of concern expressed by HHS in its comments on our use of
the word "forestall" is being raised at this time. We issued a report
in June 2007 that discussed efforts to forestall an influenza pandemic,
including the word "forestall" in the report title, on which HHS
provided written comments. At that time, HHS expressed no concern with
the term. In addition WHO has used the word in describing its efforts
to respond to a pandemic and our definition is consistent with WHO's
use of the term.
Moreover, we fail to see significant differences in the meaning of the
word "forestall" as compared to other terms and concepts contained in
other parts of HHS's comments on this report and other public comments.
For example, in its comments, HHS discussed a goal to "minimize the
impact" of a pandemic. They expressed the desire that we explicitly
state the concept of "stopping or slowing the spread of" an incipient
pandemic, rather than using the word forestall, defined as "prevent or
delay," which HHS believes is likely to be misinterpreted by the
readership. Later in its comments, HHS stated that a pandemic may be
"temporarily averted" or slowed. HHS stated in its letter that a
vaccine could "dramatically change the course" of a pandemic. While we
believe that these concepts are consistent with our use of the term
forestall when describing efforts to respond to a pandemic in such a
way as to avert, slow, mitigate, or change the course of a pandemic, we
have revised the report and defined forestall to mean containing,
delaying, or minimizing the impact of the onset of a pandemic. We have
also added discussion to the report to further clarify our use of the
term, making it clear that success in these efforts is uncertain and
that it is unlikely that a pandemic can be entirely prevented.
HHS provided other general comments on the structure and organization
of the report. HHS expressed concern that we have provided an
inadequate amount of information about influenza diagnostic tests. They
said that our emphasis on OFFLU is out of proportion to the role it
plays in recognizing when a new virus with pandemic potential has begun
to spread in humans. They further suggest that we do not adequately
distinguish between seasonal, pre-pandemic, and pandemic vaccines.
Finally, HHS stated that some information in the draft is out of date
and that they corrected many factual errors in their technical comments.
We have evaluated HHS's other comments on the structure and
organization of the report. Both their general and technical comments
suggested that we have overemphasized some issues while
underemphasizing others. They also touched upon areas where HHS does
not believe that we adequately distinguished between various aspects of
influenza response; for example, HHS commented that we do not
adequately distinguish between seasonal and pandemic influenza but also
noted that much of what is believed to be true about pandemic influenza
is based upon experience with seasonal influenza. We made changes to
the report where HHS's general and technical comments could enhance
clarity and completeness. However, this report was intended to describe
the challenges and limitations of efforts to respond to an impending
pandemic using antivirals and vaccines; it was not intended to capture
a complete inventory of the most current scientific knowledge and
developments regarding these two countermeasures. In some cases, rapid
scientific advances may have outpaced the timing of this report such
as, for example, the initiation of a new area of research not
specifically identified in the report. In other cases, there is no
consensus on the appropriate use and likely results of various medical
countermeasures, including different types of antivirals and vaccines.
Further, while we updated the report to reflect changes that occurred
while the draft report was with the agencies for comment, we disagree
with HHS that the draft contained many factual errors. In its comments,
HHS updated the information in the report in several areas, provided
additional information on some points, and suggested different areas of
emphasis in others. HHS suggested different wording in several
instances that would have made our description of certain concepts
extremely technical and not easily understood by persons not expert in
the field. In those instances, we often chose not to make the change
suggested by HHS. There were few instances of corrections of facts.
Moreover, in a meeting discussing the draft, an HHS official was
complimentary of the accuracy and completeness of the report.
The Department of State suggested in its comments that the report
should be restructured to separate discussion of antivirals and
vaccines. The comments state that these medical countermeasures are
very different from each other in their application, utility, and the
challenges the U.S. government faces in development and production of
sufficient quantities. They further commented that while the report
extensively discusses the challenges in production of adequate
quantities of medical countermeasures, it does not give adequate
consideration to the challenges of establishing protocols that would
guide the international community in the use of whatever vaccines and
antivirals are available. They also suggested that our use of the word
"forestall" is somewhat ambiguous and should be clarified.
While we did not separate the discussion of antivirals and vaccines as
the Department of State suggested, we revised the draft to ensure that
discussion of antivirals and vaccines are clearly distinguished from
one another. While antivirals and vaccines are very different from each
other, we believe that the issues involved in identifying where they
are needed, manufacturing sufficient quantities, shipping them to where
they are needed, and administering them safely, are similar enough to
merit discussing them together. We agree that the issue of establishing
protocols to guide the international community in the use of antivirals
and vaccines is an important one. However, this issue was discussed in
the draft report and the Department of State did not articulate in its
comments what information needs to be added.
The Department of State's concerns about our use of the word
"forestall" are unclear. In making this comment, the Department of
State suggests that we refer to the North American Plan for Avian and
Pandemic Influenza, approved by the United States, Canada, and Mexico.
The comments quote the plan, which states that "The North American Plan
will enhance collaboration in order to … prevent or slow the entry of a
novel (pandemic) strain of human influenza to North America." We fail
to see the meaningful difference between the words, "prevent or slow"
in the plan and "prevent or delay," which is the meaning of the word
"forestall." However, as stated earlier, we added discussion to the
report to clarify our use of the word "forestall."
We incorporated technical comments provided by HHS, the Department of
State, and WHO, as appropriate throughout the report.
As arranged with your offices, unless you publicly announce the
contents of this report earlier, we plan no further distribution of it
until 30 days after its issue date. At that time, we will send copies
of this report to the Secretary of Health and Human Services, the
Secretary of State, the Commissioner of the U.S. Food and Drug
Administration, the Director of the Centers for Disease Control and
Prevention, the Director of the National Institutes of Health, the
Director of the Office of Global Health Affairs, the Special
Representative on Avian and Pandemic Influenza at the U.S. Department
of State, and to interested congressional committees. We will also make
copies available to others upon request. In addition, the report will
be available at no charge on GAO's Web site at [hyperlink,
http://www.gao.gov].
If you or your staff have any questions about this report, please
contact Marcia Crosse at (202) 512-7114 or crossem@gao.gov or David
Gootnick at (202) 512-3149 or gootnickd@gao.gov. Contact points for our
Offices of Congressional Relations and Public Affairs may be found on
the last page of this report. GAO staff who made major contributions to
this report are listed in appendix III.
Singed by:
Marcia Crosse:
Director, Health Care:
Signed by:
David Gootnick:
Director, International Affairs and Trade:
[End of section]
Appendix I: Comments from the Department of Health and Human Services:
Department Of Health & Human Services:
Office of the Assistant Secretary for Legislation:
Washington, DC 20201:
September 17, 2007:
Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
Washington, DC 20548:
Dear Ms. Crosse:
Enclosed are the Department's comments on the U.S. Government
Accountability Office's (GAO) draft report entitled, "Influenza
Pandemic: Efforts Under Way to Address Constraints on Using Antivirals
and Vaccines to Forestall a Pandemic (GAO 07-1052).
The Department provided several technical comments directly to your
staff.
The Department appreciates the opportunity to review and comment on
this report before its publication.
Sincerely,
Signed by:
Rebecca Hemarel for Vincent J. Ventimiglia:
Assistant Secretary for Legislation:
[End of letter]
General Comments Of The Department Of Health And Human Services (HHS)
on The Government Accountability's Office's (GAO) Draft Report
Entitled: Influenza Pandemic: Efforts Under Way To Address Constraints
On Using Antivirals And Vaccines To Forestall A Pandemic (GAO-07-1052):
HHS appreciates GAO's work on several different reports concerning the
important topic of influenza pandemic preparedness. Although we
recognize that the topics of vaccines and antivirals are very important
in their own right, GAO-07-1052 clearly has lost the larger context of
all efforts with respect to pandemic preparedness, and the presentation
of the antiviral and vaccine strategies and implementation plans are
not captured. While this context can (and should) be restored to this
document, from the outset, the premise that a pandemic can be
"forestalled" is not one widely held by the public health or scientific
community. GAO should revisit this premise as it is misguided and
misleading.
While the H5N1 influenza virus is in the news less often than it was
just a year ago, we remain on alert for a human influenza pandemic (WHO
Phase 3, Pandemic Alert) with the virus now responsible for animal
outbreaks and killed hundreds of millions of chickens in 60 countries,
up from just a dozen two years ago. Worldwide, over 300 human cases
have been confirmed in 12 of those countries. For those who have been
infected, the disease is very serious – overall 61 % of the human cases
have been fatal. During this period, the H5N1 virus has evolved.
Currently, the H5N1 viruses can be divided into two distinct clades --
clade 1 and clade 2 – with the latter branching into three subclades.
While this is especially relevant to the selection of a vaccine target,
it reinforces the plasticity of this RNA virus and serves as a constant
reminder that with this virus becoming endemic among many avian species
around the world, with each viral replication cycle comes the
possibility that the next generation of virus could be the one that
sparks a human pandemic.
Yet despite all that it has shown us in the past several years,
scientists do not know whether this virus is capable of sparking a
pandemic and if so, how severe it might be. Recent reviews of the
natural history of past pandemics and our expanded investments in the
scientific underpinnings of this virus provide new insights into how we
might minimize the impact of a pandemic and, for the first time in
history we have the potential to do this. However, unlike the SARS
virus, a different respiratory virus that recently showed us the
potential for rapid global spread of disease in the 21st century,
unless the circumstances arc ideal, few believe that a developing
pandemic can be stopped in its tracks.
The majority of human cases to date can be attributed to exposure to
infected poultry. However, there have been episodes where it appears
likely that humans were the source of the infection in other humans,
but efficient and sustained transmission from person-to-person-to-
person did not occur. Although there arc many uncertainties about the
future of the H5N1 virus itself, based on what we have learned about
pandemics in the past and what we now know about the molecular
evolution of influenza viruses the only certainty about influenza
pandemic is that will continue to occur since novel influenza viruses
will continue to emerge and will continue to be a threat. Therefore, we
must prepare. Because of what is at stake, it is appropriate that the
Congress asked GAO to assess our progress.
Our preparations are broad and deep. As outlined in the National
Strategy for Pandemic Influenza, they affect all Departments and
Agencies, State, Local and Tribal Governments, communities, families
and individuals. Therefore, we appreciate that GAO is reviewing many
aspects of the nation's pandemic preparedness activities and recognize
that this report, focused on vaccines and influenza antiviral drugs is
only one piece of a their broader scope of work on this topic. However,
we caution that analysis of vaccines and antiviral drugs is part of a
larger, integrated whole, so viewing them outside of the broader
context is likely to raise other questions and issues.
We believe that the current draft of GAO-07-1052 suffers from the
following deficiencies:
A limited exploration, understanding and statement of fact regarding
the overall U.S. Government (USG) strategy for the use of influenza
vaccines and antivirals before and during a pandemic:
* The USG approach to pandemic preparedness is a very dynamic one and
has advanced significantly in the last six months, in part because
important substantive new data has emerged concerning the use of
adjuvants with pre-pandemic vaccines. While we recognize that any
report will necessarily be somewhat out of date by the time it is
published, this report lacks essential information to properly inform
the intended audience.
* The "mix and match" stockpiling strategy now in place must be
included.
A fundamental misunderstanding concerning forestalling a pandemic using
vaccines and antivirals:
* The concept that antivirals (and possibly vaccines under certain very
specific circumstances) might be used to stop an incipient pandemic or
to slow the spread should be explicitly stated instead of using the
word forestalled in a way that is very likely to be misinterpreted by
the readership. Further, GAO should acknowledge that there is not
experience in preventing an incipient pandemic.
* The emergence of a virus with the ability to be transmitted from
human-to-human in an efficient and sustained manner cannot be
forestalled by using vaccines and antivirals.
* Because avian viruses such as H5N1 are a likely source of pandemics,
without effectively eliminating the virus in avian populations, the
potential threat to humans will likely persist. Thus theoretically the
only way to truly forestall a human pandemic would be to eliminate the
avian reservoir. This concept is not included in GAO-07-1052.
Our preparations also involve the development and analysis of new
science relevant to vaccines and antivirals and a number of novel
influenza viruses (including H5N1 virus). We are also concerned that
this report fails to draw bright lines between what we know about
seasonal influenza, the novel forms of influenza virus that have
already appeared, and pandemics. What we know about how antiviral drugs
and influenza vaccines perform is largely drawn from our long
experience with these products during seasonal influenza. For example,
the neuraminidase inhibitor drugs (oseltamivir and zanamavir) were
initially licensed for use by the FDA for the treatment of
uncomplicated seasonal influenza and if administered within 48 hours of
the onset of symptoms, their impact was to reduce the time to freedom
from illness by 1.5 days compared to placebo. How they will perform
against a pandemic influenza virus cannot be predicted, but as there
are currently no better options, stockpiles are being established.
In addition, we are also concerned by the expectation that GAO has set
in its assumption that a pandemic can be forestalled and that vaccines
and antivirals are only tools necessary to do so. While preventing a
pandemic from occurring is the goal that all strive for, whether it can
actually be achieved is not known. Mathematical models of the spread of
a novel influenza virus hold out the hope that under the right
circumstances – early identification of the emergence of a pandemic
outside of a densely populated urban setting – an emerging pandemic
might be contained, assuming that antiviral drugs that are used are
available, effective both as treatment and as prophylaxis, are used
strategically and can get to where they need to be before a pandemic
spark becomes a forest fire.
Led by the World Health Organization and in concert with our global
partners, the strategy for such a rapid response is being refined (WHO
Pandemic Influenza Draft Protocol for Rapid Response and Containment,
May 30, 2006). Antiviral drugs may well be an important component and
make such an effort most effective but their availability alone is
insufficient to accomplish the task. Therefore, we caution those who
may conclude that the establishment of national and global stockpiles
of antiviral drugs has solved the problem.
If a potential pandemic is identified early attempts at containment
should and will be attempted. Such an effort would be in the best
interest of both the affected country, and of benefit to global health
security if it is successful in containing or slowing down the
development of an emerging pandemic. Yet, there is no assurance a
containment effort will succeed. In the likely event containment fails,
the effort may still have the effect of slowing the pandemic's rate of
spread. If containment succeeds, a pandemic may be at least temporarily
averted.
In contrast, as a truly preventive health measure only a vaccine will
have the capability of dramatically changing the course of an influenza
pandemic. Emerging vaccine production technologies (e.g., cell culture)
and new approaches to the vaccine development (e.g., vaccine adjuvants
and recombinant vaccines) may well influence the time it takes to
develop and produce a pandemic vaccine. Many of these approaches are
very promising and studies being conducted by HHS and those of many
vaccine companies will provide the data to better judge which of these
approaches are the most likely to be effective, but these vaccines are
not yet sufficiently advanced to prevent a pandemic in its tracks if it
occurred tomorrow.
The addition of a very small amount of information about influenza
diagnostic test development is confusing within the context of the
subject and structure of the document:
* The efforts to develop diagnostic tests go well beyond the
information presented here which is not factually correct as noted in
the editorial comments. This section should be excised or expanded to
be complete and factually correct.
The emphasis on OFFLU is totally out of proportion to the role they
play in recognizing when a new virus with pandemic potential has begun
to spread in humans. This recognition will occur on the international
and domestic human influenza arena, not in the veterinary context:
* OFFLU is given great emphasis in this document on page 33 and again
on page 52. It must be understood that OFFLU does not monitor human
infections and plays a limited role in international surveillance for
influenza viruses that infect humans.
* The role of human influenza surveillance is neglected in this
document relative to the importance of the detection and monitoring of
person-to-person spread of a new pandemic virus. This detection will
trigger the use of vaccines and antivirals. HHS will append a
spreadsheet outlining all of the international activities for influenza
surveillance and capacity building relevant to human health
accomplishments which dwarf what OFFLU has done in the context of
pandemic preparedness.
* The emphasis on OFFLU is just one example where the auditors spoke
with an articulate person from this organization but were unable to put
the information into the proper context of the threat of pandemic
influenza and what the USG and others are doing globally.
Structural weakness in the document that will confuse the Congressional
audience about the differences between seasonal and pre-pandemic or
pandemic vaccines:
* The concept that vaccines could be used to help with limiting the
spread of an incipient influenza pandemic is a rather new one and has
not been fully explored and over emphasis is placed on vaccines within
this context.
* The use of pre-pandemic vaccines is also controversial but one that
is not explored factually in this document.
Although seasonal, pre-pandemic and pandemic vaccines are defined on
page 10, the authors are not consistent throughout the document in
defining for their audience the use and target populations for these
vaccines.
Information that is out of date:
* Some information dates from 2005 and other dates from 2006 and these
pieces of information are out of date and misrepresent the current
status.
Many factual errors are in GAO-07-1052:
* Many errors of fact are corrected in the technical comments which are
provided to GAO in a separate document. In addition, we have attempted
to point out areas where additional fact finding should be done by the
auditors in order to present to Congress an accurate and more complete
picture of USG activities.
We hope that this information as well as the technical comments
attached to this response is useful to you. Please do not hesitate to
contact us if we can be of further assistance.
[End of section]
Appendix II: Comments from the Department of State:
United States Department of State:
Assistant Secretary for Resource Management and Chief Financial
Officer:
Washington, D.C. 20520:
Ms. Jacquelyn Williams-Bridgers:
Managing Director International Affairs and Trade:
Government Accountability Office:
441 G Street, NW:
Washington, D.C. 20548-0001:
September 18, 2007:
Dear Ms. Williams-Bridgers:
We appreciate the opportunity to review your draft report, "Influenza
Pandemic: Efforts Under Way to Address Constraints on Using Antivirals
and Vaccines to Forestall a Pandemic," GAO Job Code 290618.
The enclosed Department of State comments are provided for
incorporation with this letter as an appendix to the final report.
If you have any questions concerning this response, please contact Dan
Singer, Senior Policy Advisor, Office of Avian Influenza Action Group,
at (202) 312-9780.
Sincerely,
Signed by:
Sid Kaplan (Acting):
cc: GAO — Thomas Conahan:
G/AIAG – John Lange:
State/OIG – Mark Duda:
[End of letter]
Department of State Comments on GAO Draft Report:
Influenza Pandemic: Efforts Underway to Address Constraints on Using
Antivirals and Vaccines to Forestall a Pandemic (GAO-07-1052, GAO Code
290618):
Thank you for the opportunity to review and comment on the draft report
"Influenza Pandemic: Efforts Underway to Address Constraints on Using
Antivirals and Vaccines to Forestall a Pandemic."
The report in its current draft would benefit from major restructuring.
One particular problem is the frequent jump in the text from discussion
of antivirals to discussion of vaccines. These medical countermeasures
are very different from each other in their application, utility, and
the challenges the U.S. Government faces in development and production
of sufficient quantities. The paper would be clearer if all issues
pertaining to antivirals were discussed, then all issues pertaining to
vaccines, with appropriate sections before and after to deal with a few
cross-cutting issues.
The use of the word "forestall" is somewhat ambiguous and should be
clarified, since the definitions of forestall include such distinct
concepts as to prevent or to hinder (delay). It may be useful to note
that the North American Plan for Avian and Pandemic Influenza, approved
by the United States, Canada and Mexico, makes clear the distinction
between: (1) containing an incipient pandemic and thereby preventing a
global pandemic; and, if containment fails, (2) delaying the arrival of
the pandemic influenza in this region. The Plan states, "The North
American Plan will enhance collaboration in order to...prevent or slow
the entry of a novel strain of human influenza to North America."
The report discusses extensively the challenges in production of
adequate quantities of medical countermeasures. Proportionally, it does
not give adequate consideration to the challenges of establishing
protocols which would guide the international community in the use of
whatever vaccines and antivirals are available. At the moment, there is
not an international consensus on how antivirals or vaccine would be
deployed, at what stage, and to whom, and this is a larger issue than
the problem of clinical trials, which is addressed in the report. The
development of international guidance for the use of antivirals and
especially pre-pandemic vaccines could be addressed in the document,
along which what the U.S. Government is doing to promote the
development of such guidance (such as funding the World Health
Organization (WHO) to write the guidance, providing staff to WHO, and
directly promoting our own views, such as the guidelines on community
mitigation during a pandemic.)
[End of section]
Appendix III: GAO Contacts and Staff Acknowledgments:
GAO Contacts:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
David Gootnick, (202) 512-3149 or gootnickd@gao.gov:
Acknowledgments:
In addition to the contacts above, Thomas Conahan, Assistant Director;
Celia Thomas, Assistant Director; Robert Copeland; Etana Finkler; David
Fox; Cathy Hamann; R. Gifford Howland; Michael McAtee; Jasleen Modi;
Syeda Uddin; and George Bogart made key contributions to this report.
[End of section]
Related GAO Products:
Influenza Vaccine: Issues Related to Production, Distribution, and
Public Health Messages. GAO-08-27. Washington, D.C.: October 31, 2007.
Influenza Pandemic: Opportunities Exist to Address Critical
Infrastructure Protection Challenges That Require Federal and Private
Sector Coordination. GAO-08-36. Washington, D.C.: October 31, 2007.
Influenza Pandemic: Further Efforts are Needed to Ensure Clearer
Federal Leadership Roles and an Effective National Strategy. GAO-07-
781. Washington, D.C.: August 14, 2007.
Influenza Pandemic: DOD Combatant Commands' Preparedness Efforts Could
Benefit from More Clearly Defined Roles, Resources, and Risk
Mitigation. GAO-07-696. Washington, D.C.: June 20, 2007.
Influenza Pandemic: Efforts to Forestall Onset Are Under Way;
Identifying Countries at Greatest Risk Entails Challenges. GAO-07-604.
Washington, D.C.: June 20, 2007.
Avian Influenza: USDA Has Taken Important Steps to Prepare for
Outbreaks, but Better Planning Could Improve Response. GAO-07-652.
Washington, D.C.: June 11, 2007.
The Federal Workforce: Additional Steps Needed to Take Advantage of
Federal Executive Boards' Ability to Contribute to Emergency
Operations. GAO-07-515. Washington, D.C.: May 4, 2007.
Financial Market Preparedness: Significant Progress Has Been Made, but
Pandemic Planning and Other Challenges Remain. GAO-07-399. Washington,
D.C.: March 29, 2007.
Influenza Pandemic: DOD Has Taken Important Actions to Prepare, but
Accountability, Funding, and Communications Need to be Clearer and
Focused Departmentwide. GAO-06-1042. Washington, D.C.: September 21,
2006.
Influenza Pandemic: Applying Lessons Learned from the 2004-05 Influenza
Vaccine Shortage. GAO-06-221T. Washington, D.C.: November 4, 2005.
Influenza Vaccine: Shortages in 2004-05 Season Underscore Need for
Better Preparation. GAO-05-984. Washington, D.C.: September 30, 2005.
Influenza Pandemic: Challenges in Preparedness and Response. GAO-05-
863T. Washington, D.C.: June 30, 2005.
Influenza Pandemic: Challenges Remain in Preparedness. GAO-05-760T.
Washington, D.C.: May 26, 2005.
Flu Vaccine: Recent Supply Shortages Underscore Ongoing Challenges. GAO-
05-177T. Washington, D.C.: November 18, 2004.
Emerging Infectious Diseases: Review of State and Federal Disease
Surveillance Efforts. GAO-04-877. Washington, D.C.: September 30, 2004.
Emerging Infectious Diseases: Asian SARS Outbreak Challenged
International and National Responses. GAO-04-564. Washington, D.C.:
April 28, 2004.
Global Health: Challenges in Improving Infectious Disease Surveillance
Systems. GAO-01-722. Washington, D.C.: August 31, 2001.
Flu Vaccine: Supply Problems Heighten Need to Ensure Access for High-
Risk People. GAO-01-624. Washington, D.C.: May 15, 2001.
Influenza Pandemic: Plan Needed for Federal and State Response. GAO-01-
4. Washington, D.C.: October 27, 2000.
[End of section]
Footnotes:
[1] WHO is the United Nations agency for health. It is responsible for
coordinating the global response to human cases of H5N1, monitoring the
spread of the disease, and determining when a virus has caused a global
pandemic. It also provides the international community with guidelines,
procedures, and recommendations on addressing infectious disease
outbreaks, including H5N1.
[2] Antivirals can prevent or reduce the severity of a viral infection,
such as influenza. Vaccines are used to stimulate the production of an
immune system response to protect the body from disease.
[3] The Asian Development Bank provides funding and technical
assistance aimed at improving the welfare of people in the Asia-Pacific
region. WHO has stated the Asian Development Bank has become a major
partner in providing financial assistance to support WHO's pandemic
response activities.
[4] Members of the IFPMA Influenza Vaccine Supply International Task
Force represent more than 95 percent of worldwide influenza vaccine
production.
[5] GAO, Influenza Pandemic: Efforts to Forestall Onset Are Under Way;
Identifying Countries at Greatest Risk Entails Challenges, GAO-07-604
(Washington, D.C.: June 20, 2007).
[6] Seasonal influenza is an outbreak of influenza that occurs every
year. There are two influenza seasons, one in the northern hemisphere
and one in the southern hemisphere. The influenza season in the
northern hemisphere is from November to April while the influenza
season in the southern hemisphere is from May to October. An epidemic
is the occurrence in a community or region of cases of an illness in
excess of what is normally expected.
[7] People aged 65 years and older, people of any age with chronic
medical conditions, children younger than 2 years, and pregnant women
are generally more likely than others to develop severe complications
from seasonal influenza.
[8] In addition to humans, influenza A viruses can infect a variety of
other animals including horses, pigs, sea mammals, and birds. In this
report, we differentiate between human influenza and animal influenza.
Evidence suggests that all human influenza A viruses originate from
influenza A viruses in wild waterfowl.
[9] Sixteen types of HA or H (hemagglutinin) proteins and 9 types of NA
or N (neuraminidase) proteins have been identified. Each combination of
these proteins (for example, H5N1) is known as a subtype.
[10] Pandemic influenza can emerge through two principal mechanisms:
reassortment and adaptive mutation. Reassortment is the mixing of human
influenza and animal influenza viruses within an animal or human to
create a new human influenza A subtype. Adaptive mutation involves
changes in the virus whereby a virus gradually acquires the changes
needed to improve its transmissibility among humans. If such changes
result in a new influenza A virus subtype that can infect humans and
spread easily from person to person, an influenza pandemic can occur.
[11] Pandemics vary in severity. For example, the pandemic of 1918-1919
was more severe than the last two pandemics (in 1957 and 1968).
[12] In the past, influenza pandemics have spread worldwide within 6 to
9 months. However, WHO has stated that given the current volume of
international travel, it is likely that a pandemic would spread more
quickly.
[13] H5N1 influenza is caused by influenza viruses that occur naturally
among wild birds. All types of birds are susceptible to the virus, but
outbreaks occur most often in chickens and turkeys. The H5N1 subtype is
deadly to domestic fowl. Currently, humans are only rarely affected.
[14] While H5N1 is considered the most likely subtype to cause a
pandemic at this time, experts have also cited the subtypes H2N2, H7N7,
and H9N2 as having pandemic potential.
[15] The case fatality rate is defined as the number of people who die
of a disease divided by the number of people who have the disease.
[16] According to HHS and WHO, there have been a limited number of
human cases in which human-to-human transmission cannot be ruled out.
However, H5N1 has not yet demonstrated an ability to spread efficiently
among humans.
[17] An antibody is a molecule produced by the immune system that helps
fight infections.
[18] The ability of influenza vaccine to protect a person depends on
the age and health status of the person getting the vaccine, and the
similarity or "match" between the virus strains in the vaccine and
those in circulation. When the vaccine and circulating virus are well-
matched, influenza vaccines will prevent illness in approximately 70 to
90 percent of healthy adults under the age of 65. The protection drops
to about 30 to 40 percent for the elderly. Vaccine effectiveness can
also be lower for individuals with underlying medical conditions such
as compromised immune systems.
[19] We use the term seed virus to indicate the modified virus from
which subsequent vaccine production for that strain is derived.
[20] The time required to produce vaccines depends, in part, on the
number of viral strains in the vaccine, satisfactory growth and yield
of the virus in chicken eggs, the number of doses required to build
immunity, and access to raw materials. All other things being equal,
vaccines that include a single strain can be produced in less time and
in greater quantities than vaccines containing multiple strains because
no additional time is needed to produce and combine additional strains.
Other factors that affect timing include testing by FDA and
manufacturers to determine vaccine strength and the development of a
reagent for such testing. A reagent is a substance used in a chemical
reaction to detect, measure, examine, or produce other substances.
Reagents are used to determine the purity and strength of influenza
vaccine, and must be developed each year for the specific new vaccine.
[21] A pre-pandemic vaccine may have both pre-pandemic and pandemic
use. For example, a pre-pandemic vaccine might be given to those at
high risk of exposure prior to a pandemic. The same vaccine might also
be used to vaccinate critical workforce and primary health care workers
in the early stages of a declared pandemic when a matched pandemic
vaccine is not available.
[22] Research is also currently underway to develop what is called a
universal vaccine, which would protect against multiple influenza
strains. However, such a vaccine does not currently exist.
[23] The five vaccines and their manufacturers were Fluarix
(GlaxoSmithKline Biologicals), FluLaval (ID Biomedical Corporation, a
subsidiary of GlaxoSmithKline Biologicals), FluMist (MedImmune
Vaccines, Inc.), Fluvirin (Novartis Vaccines and Diagnostics, Inc.),
and Fluzone (sanofi pasteur, Inc.) The policy of sanofi pasteur is to
spell its name without capital letters.
[24] The switch to pandemic vaccine production is a decision that
manufacturers will make together with public health officials. This
switch will impact the availability of the following year's seasonal
vaccine since production facilities will be used to produce pandemic
vaccine instead of seasonal vaccine. If such a decision is made and the
pandemic does not occur, the pandemic vaccine will not likely protect
against the following year's seasonal influenza. However, if a pandemic
does occur and the decision is late, then that will add to the delay in
the availability of a pandemic vaccine.
[25] Adamantanes, also known as M2-ion channel inhibitors, are less
expensive than neuraminidase inhibitors. Amantadine and rimantadine are
no longer under patent protection and are referred to by their
scientific (that is, generic) names.
[26] Tamiflu and Relenza are both under patent protection in some
countries, including the United States, and therefore are referred to
by their brand names instead of their scientific names, oseltamivir and
zanamivir, respectively.
[27] Antiviral resistance is the result of viruses changing in ways
that reduce or eliminate the effectiveness of antiviral agents to treat
or prevent infections. Antiviral resistance can emerge due to genetic
changes in the virus from either natural mutation or as a result of the
use of antivirals, including antiviral misuse such as not completing
the full treatment course. According to HHS, antiviral resistance is
one of several factors that could limit the effectiveness of
antivirals. In addition, not all viral changes leading to reduced
effectiveness of antivirals would generally be termed resistance. In
this report, we use resistance to refer to changes in the virus that
result in reductions in the effectiveness of antivirals in responding
to influenza outbreaks.
[28] However, concerns regarding Tamiflu and Relenza have recently
increased. On November 13, 2006, FDA announced a change to the
prescribing information for Tamiflu to include a precaution about
neuropsychiatric events. The revision is based on postmarketing reports
(mostly from Japan) of self-injury and delirium with the use of Tamiflu
in patients with influenza. The reports were primarily among pediatric
patients. On November 27, 2007, FDA's Pediatric Advisory Committee
recommended stronger warning labels for both Tamiflu and Relenza
because of reports of neuropsychiatric problems in children and teens.
[29] The patent holders for Tamiflu and Relenza, Gilead Sciences and
Biota Holdings Limited, respectively, have licensed these drugs to
Roche and GlaxoSmithKline.
[30] Tamiflu and Relenza are both patent protected in some countries,
which limits the manufacture, use, sale, offering to sell, and
importation of these drugs in those countries. Both Tamiflu and Relenza
are patent protected in the United States. However, they are not patent
protected everywhere. For example, generic drug makers in Bangladesh,
India, and Taiwan manufacture a generic version of Tamiflu. These
products can be sold in countries without patent protection for
Tamiflu.
[31] In addition to the Departments of Agriculture, Defense, Health and
Human Services, and State and the U.S. Agency for International
Development, representatives from the Department of Homeland Security,
the National Security Council, the Homeland Security Council, and U.S.
intelligence agencies attend working group meetings. The Department of
the Treasury has not been a regular participant. However, the
Department of the Treasury has worked with U.S. executive directors at
the World Bank, the Asian Development Bank, and other international
financial institutions to encourage and support these entities' efforts
to address influenza threats.
[32] See Departments of Labor, Health and Human Services, and
Education, and Related Agencies Appropriations Act, 2006, Pub. L. No.
109-149, 119 Stat. 2833, 2857 (funds not limited to purposes related to
pandemic or avian influenza); Department of Defense, Emergency
Supplemental Appropriations to Address Hurricanes in the Gulf of
Mexico, and Pandemic Influenza Act, 2006, Pub. L. No. 109-148, 119
Stat. 2680, 2783, 2786; Emergency Supplemental Appropriations Act for
Defense, the Global War on Terror and Hurricane Recovery, 2006, Pub. L.
No. 109-234, 120 Stat. 479 (includes $30 million to be transferred to
the U.S. Agency for International Development). HHS also received
appropriations available for pandemic-influenza-related purposes, among
other purposes, totaling $50 million in fiscal year 2004, $182 million
in fiscal year 2005, and $100 million in fiscal year 2007. 2004:
Consolidated Appropriations Act, 2004, Pub. L. No. 108-199, 118 Stat.
3, 251; 2005: Consolidated Appropriations Act, 2005, Pub. L. No. 108-
447, 118 Stat. 2809, 3138, Emergency Supplemental Appropriations Act
for Defense, the Global War on Terror, and Tsunami Relief, 2005, Pub.
L. No. 109-13, 119 Stat. 231, 276, 280; 2007: Revised Continuing
Appropriations Resolution, 2007, Pub. L. No. 110-5, 121 Stat. 8, 33.
Many of these appropriations remain available until expended, that is
without fiscal year limitation.
[33] WHO, WHO Interim Protocol: Rapid operations to contain the initial
emergence of pandemic influenza (Geneva: WHO, Oct. 2007), [hyperlink,
http://www.who.int/entity/csr/disease/avian_influenza/guidelines/RapidCo
ntProtOct15.pdf] (accessed Oct. 27, 2007). This rapid containment
strategy is one of the five major strategic actions that form the basis
of the WHO strategic action plan for pandemic influenza. (Geneva: WHO,
May 2007), [hyperlink,
http://www.who.int/csr/resources/publications/influenza/WHO_CDS_EPR_GIP_
2006_2/en/index.html] (accessed July 19, 2007). In addition to these
documents, we also have drawn on a number of other WHO documents
dealing with forestalling a pandemic.
[34] That strategy, released in November 2005, has three broad pillars:
(1) preparedness and communications, (2) surveillance and detection,
and (3) response and containment. In August 2007, the United States,
Canada, and Mexico issued the North American Plan for Avian & Pandemic
Influenza, which outlines how the three countries intend to work
together to combat an outbreak of avian influenza or an influenza
pandemic in North America.
[35] An exception was the U.S. government decision to mass vaccinate
the public against an outbreak of swine flu in New Jersey in 1976. That
effort was halted when a small apparent risk emerged of contracting
Guillain-Barre syndrome--an inflammatory disorder that can cause
paralysis--from the swine flu vaccine, and there was no extensive
spread of the influenza strain of concern.
[36] WHO has stated that there are three opportunities for using
antivirals. The first, and present situation, is when antivirals are
used to treat infected patients and to prevent infection in close
contacts, including family members and health care workers. The second
is when surveillance indicates that the transmissibility of the virus
among humans is beginning to become more efficient. In this
circumstance, administration of antivirals to all members of a
community in which clusters of cases are occurring might either stop
the virus from further improving its transmissibility or delay
international spread. The third opportunity is once a pandemic has been
declared. Pending the availability of vaccines, antivirals will be the
principal medical intervention for reducing morbidity and mortality.
[37] The four WHO Collaborating Centres are located in the United
States, Australia, Japan, and the United Kingdom. CDC is the
Collaborating Centre in the United States.
[38] Reagents are used to determine the purity and strength of
influenza vaccine.
[39] There does not appear to be agreement on the time needed to
produce a pandemic vaccine. In a document distributed for a November
2007 meeting on pandemic influenza preparedness, WHO stated that the
total approximate time to produce an H5N1 vaccine is 28 to 52 weeks.
[40] For an influenza virus, genetic sequencing reveals the complete
genetic blueprint (sequence) of the virus.
[41] GAO-07-604, 61.
[42] Point-of-care testing refers to a laboratory test that can be
performed outside of a laboratory facility, with results available to
doctors and patients within minutes.
[43] The dosage for current seasonal vaccines is 15 micrograms per
strain in the trivalent vaccine, for a total dosage of 45 micrograms.
However, it is unknown what dosage would be effective against a
pandemic strain.
[44] A treatment course is the number of doses needed to treat a person
that has been infected with an influenza virus. A treatment course for
Tamiflu contains 10 capsules taken over the course of 5 days.
[45] A preventative course would be given to individuals within the
containment zone that may have been exposed to the virus. In this case,
a preventative course for Tamiflu would be 20 capsules taken over the
course of 20 days.
[46] HHS, Pandemic Planning Update IV (Washington, D.C.: 2007).
[47] Another benefit resulting from seasonal vaccination is that it
would decrease the chance of confusing the diagnosis of cases of
seasonal influenza with H5N1.
[48] This represents an increase in capacity of 215 million doses over
the 350 million dose capacity in 2006.
[49] GAO, Influenza Vaccine: Shortages in 2004-05 Season Underscore
Need for Better Preparation, GAO-05-984 (Washington, D.C.: Sept. 30,
2005), 3.
[50] According to IFPMA, many noninfluenza vaccines are manufactured in
large volumes and used around the world, including in developing
countries. This is not the case with influenza vaccine due primarily to
low demand for seasonal influenza vaccines in such countries and the
unpredictability of the occurrence of pandemic influenza. For these
reasons, manufacturing capacity for seasonal influenza vaccines in
developing countries has been limited and expansion is considered to be
economically difficult.
[51] Countries creating production infrastructure may require starting
materials, such as reagents, to develop and produce vaccines and may
need assistance in establishing new facilities. A reagent is a
substance used in a chemical reaction to detect, measure, examine, or
produce other substances. Reagents are used to determine the purity and
strength of influenza vaccine.
[52] GAO-07-604, 61.
[53] Sandra Mounier-Jack and Richard J. Coker, "How Prepared is Europe
for Pandemic Influenza? Analysis of National Plans," The Lancet, vol.
367, no. 9520 (2006) and Richard Coker and Sandra Mounier-Jack,
"Pandemic Influenza Preparedness in the Asia-Pacific Region," The
Lancet, vol. 368, no. 9538 (2006).
[54] In a follow-up study, the authors found that Europe had become
better prepared for a pandemic. However, they noted that countries'
plans on antivirals and vaccines varied and that operational planning
remained weak. For example, they found that determining how to deliver
antivirals within 48 hours to individual patients remained largely
unresolved. Many countries are delegating this responsibility to local
officials but are providing little guidance. Similarly, although most
study countries had prioritized groups for receiving antivirals and
vaccines, the details on how these policies would be implemented had
not been put in place. See Sandra Mounier-Jack, Ria Jas, and Richard
Coker, "Progress and Shortcomings in European National Strategic Plans
for Pandemic Influenza," Bulletin of the World Health Organization,
vol. 85, (2007). Published online ahead of print at [hyperlink,
http://www.who.int/bulletin/published_ahead_of_print/en/index.html]
(accessed Oct. 15, 2007).
[55] Economic development refers to the process of raising the level of
prosperity and material living in a society through increasing the
productivity and efficiency of its economy.
[56] See GAO-05-984, 17. In the United States, influenza vaccine
production and distribution are largely private-sector activities. HHS
has limited authority to control vaccine distribution directly.
Manufacturers sell influenza vaccine to resellers (such as medical
supply distributors and pharmacies), federal agencies, state and local
public health departments, or directly to providers. Individuals can
obtain an influenza vaccination at a number of places, including
physicians' offices, public health clinics, nursing homes, and
nonmedical locations such as workplaces or retail outlets. During the
2004-2005 influenza season, CDC took actions in addition to the
allocation plan discussed to deal with the vaccine shortage. For
example, CDC developed a revised recommendation on who should be
vaccinated, so that vaccine could be directed to those at high risk and
to other priority groups, and worked with one manufacturer to increase
production.
If the Secretary of HHS determines and declares a public health
emergency, the Public Health Service Act authorizes the Secretary to
"take such action as may be appropriate" to respond. According to the
act, to declare a pubic health emergency, the Secretary must determine
that (1) a disease or disorder presents a public health emergency, or
(2) a public health emergency, including significant outbreaks of
infectious disease or bioterrorist attacks, otherwise exists. The
federal government and some states are currently building
pharmaceutical stockpiles that they would control.
[57] If granted liability protection, manufacturers generally would not
have to pay compensation to individuals injured by a vaccine. IFPMA's
Influenza Vaccine Supply International Task Force issued a position
statement in May 2006, calling for a waiver of liability for the
manufacturing and use of pandemic vaccines.
[58] The International Health Regulations are legally binding
agreements on all 193 WHO member states who have not rejected them (or
who have not raised reservations about them) and on all nonmember
states of WHO that have agreed to be bound by them. Originally adopted
in 1951 and named the International Sanitary Regulations, the
Regulations were replaced by and renamed the International Health
Regulations in 1969. Other than minor modifications in 1973 and 1981,
the Regulations had not been revised again until the current revisions.
The purpose and scope of the revised regulations are to prevent,
protect against, control, and provide a public health response to the
international spread of disease in ways that are commensurate with and
restricted to public health risks, and which avoid unnecessary
interference with international traffic and trade. Although the revised
regulations do not include an explicit enforcement mechanism, WHO
indicates that public knowledge and "peer pressure" within the global
community are expected to provide powerful incentives for compliance.
[59] The revised International Health Regulations went into effect for
the United States on July 17, 2007.
[60] Fifty-eighth World Health Assembly, agenda item 13.1, Revision of
the International Health Regulations, May 23, 2005, [hyperlink,
http://www.who.int/gb/ebwha/pdf_files/WHA58/A58_55-en.pdf] (accessed
Nov. 16, 2007).
[61] Despite the provisions not going into effect until June 2007, in
May 2006 the World Health Assembly--the supreme decision-making body of
WHO--requested that its member states comply immediately, on a
voluntary basis, with provisions of the revised Regulations considered
relevant to the risk posed by pandemic influenza.
[62] OIE stands for Office International des Epizooties--the
organization's original name, adopted at its founding in 1924. In 2003,
the organization decided to begin using the common name World
Organisation for Animal Health while retaining the OIE acronym. OIE is
a multilateral organization but is not part of the United Nations.
[63] By putting influenza sequences in the public domain rather than in
restricted databases, more researchers have access to the information
and can work to better understand how influenza viruses evolve, spread,
and cause disease.
[64] An antigen is any foreign substance that stimulates the body's
immune system to produce antibodies.
[65] Zoonoses are diseases that are transferable from animals to
humans.
[66] The World Health Assembly is the supreme decision-making body of
WHO.
[67] The Asia-Pacific Economic Cooperation consists of 21 economies
including those of China, Indonesia, and Vietnam.
[68] An official stated that the agreement must ensure that developing
countries will receive equitable access to affordable vaccines made
from the samples they share.
[69] H5 is 1 of 16 hemagglutinin proteins that can make up an influenza
virus. It can be combined with 1 of 9 types of neuraminidase proteins
to form an influenza subtype. For example, H5N1 is an influenza
subtype.
[70] A reference laboratory conducts tests for other laboratories. A
public health laboratory is a facility with the equipment and staff
needed to conduct public health assessments and respond to emergency
public health issues.
[71] WHO has suggested that this be one component of a larger effort to
increase vaccine production capacity. See WHO, Global pandemic
influenza action plan to increase vaccine supply (Geneva: WHO, Sept.
2006), [hyperlink,
http://www.who.int/vaccinesocuments/DocsPDF06/863.pdf] (downloaded Oct.
26, 2006).
[72] The current HHS policy is to administer the H5N1 pre-pandemic
vaccine stockpile to critical workforce members at the onset of an
influenza pandemic caused by an H5N1-like virus. Studies are being
conducted to determine if there may be value in immunizing more people
at the onset of a pandemic. If so, the size of the pre-pandemic vaccine
stockpile may be expanded. In addition, the Department of Defense is
establishing, for military use, stockpiles of vaccines against H5N1 and
other influenza subtypes with pandemic potential large enough to
immunize approximately 1.35 million persons.
[73] In April 2007, Roche reported that it had received orders or
letters of intent from more than 80 countries for approximately 215
million treatment courses of Tamiflu. It had also received orders from
more than 250 corporations for about 5 million treatment courses.
[74] These sublicensees cannot use the Tamiflu name and Roche does not
ensure the quality of the products.
[75] WHO has suggested that this be one component of a larger effort to
increase vaccine production capacity. WHO estimates that $2 billion to
$9 billion would be needed for all of these activities. See WHO, Global
pandemic influenza action, [hyperlink,
http://www.who.int/vaccinesocuments/DocsPDF06/863.pdf] (accessed Oct.
26, 2006).
[76] The six countries are Brazil, India, Indonesia, Mexico, Thailand,
and Vietnam.
[77] Sanofi pasteur has invested $150 million to create a new
manufacturing facility in the United States that will allow it to
double its influenza vaccine manufacturing capacity in time for the
2008-2009 influenza season. Similarly, GlaxoSmithKline has committed
more than $2 billion to increase its vaccine and antiviral production.
[78] In September 2007, BioCryst Pharmaceuticals, Inc., reported the
preliminary results of a study of the safety and effectiveness of
peramivir in humans. The company noted that it was disappointed that
the study did not meet its primary objective of reducing the time to
lessen symptoms. However, it also stated that it had a plan to correct
the issues identified in the study and planned to continue clinical
trials.
[79] Probenecid is used to treat chronic gout and gouty arthritis.
[80] HHS noted that this vaccine may be used during the pre-pandemic
period for those at increased risk of exposure to H5N1; however, it may
also be used during the pandemic period because everyone would be
considered at increased risk for exposure to H5N1 if the pandemic
outbreak is of the H5N1 subtype.
[81] The predicted effectiveness of the pre-pandemic vaccine is based
on a measure of immune response. However, the measure is not a perfect
surrogate for immunity and is known to be imperfect even for seasonal
influenza. On the other hand, the effectiveness of seasonal influenza
vaccines is based not on a surrogate measure, but on studies examining
the actual level of protection offered from vaccination.
[82] While cell-based production methods are new for influenza
vaccines, they have been used for other vaccines such as chickenpox,
hepatitis A, polio, and shingles.
[83] Eggs for vaccine manufacturing come from producers that are
located mainly in Europe, as are vaccine manufacturers. This creates
vulnerabilities. For example, large egg suppliers based in the
Netherlands were left without eggs for vaccine production after an H7N7
influenza outbreak among chickens in that country in 2005.
[84] Researchers are also pursuing other methods to develop vaccines.
For example, DNA-based vaccines contain portions of the influenza
virus' genetic material. Potentially, these vaccines could be produced
more quickly than egg-based vaccines and provide protection against
more than one influenza strain. The first human trial of a DNA vaccine
to prevent H5N1 infection in people began in December 2006. In June
2007, NIH awarded Vical Incorporated a $6 million grant to develop a
DNA vaccine manufacturing process.
[85] A universal vaccine would protect against both seasonal and
pandemic influenza viruses. HHS has stated that successful development
of a universal vaccine would mean that individuals would need only one
influenza shot to protect them for many years (possibly for life).
[86] In April 2007, WHO's Strategic Advisory Group of Experts on
Immunization concluded that it was realistic to expect that vaccines
offering protection against multiple influenza strains could be
developed; however, no specific time frame was given. In May 2007, WHO
said that a universal vaccine might not be available in the next 5 to
10 years.
[87] Live attenuated vaccines use a weakened form of the influenza
virus to stimulate a protective immune response in the body.
[88] The global stockpile is divided and located in Switzerland, the
United Arab Emirates, and WHO regional offices. Prior to this, in 2004
Roche had donated 125,000 treatment courses, which were used by WHO in
Asian countries affected by H5N1.
[89] However, if containment is not possible, the Tamiflu would be sent
back to the U.S. stockpile of antiviral influenza medications.
[90] For example, different countries can have varying requirements for
clinical trials.
[91] According to experts, global availability of antivirals and
vaccines could be increased with coordination of different countries'
regulatory processes. According to experts, one benefit would be that
clinical trials might not have to be duplicated.
[92] Vaccines approved under this process are only approved for use in
a declared influenza pandemic. They are not approved for use prior to a
pandemic. The objective of this mechanism is to have a marketing
authorization in place that can be changed quickly in the event of a
pandemic to include the virus strain responsible, once it has been
identified. These are referred to as mock-up pre-pandemic influenza
vaccines.
[93] The goal is to approve the pandemic vaccine within 4 days after
the application is submitted. The United Kingdom Vaccine Industry Group
estimated that overall this process would allow a pandemic vaccine to
be provided 2 to 4 months faster than if a pre-pandemic vaccine had not
been approved.
[94] WHO and many national health authorities recommend annual
vaccination for a range of risk groups. These groups include those over
a nationally defined age limit (often 65 years), those with specific
chronic illnesses such as heart, lung, or kidney conditions including
asthma and diabetes, and those suffering from immunosuppression, such
as transplant patients and those with HIV. In addition, guidelines
recommend vaccination for those who may transmit influenza to high-risk
groups, such as health care workers and household contacts.
[95] WHO estimates that a total of $3 billion to $10 billion will be
required to implement its entire vaccine action plan. The other
objectives of the plan are to increase influenza vaccine production
capacity and to promote research and development for new influenza
vaccines. In March 2007, WHO announced that in mid-2007 an independent
steering committee with representation of both developing and
industrialized countries would be formed to oversee implementation of
the plan. Canada will provide support for the committee and its work.
[96] GAO-07-604.
[End of section]
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